59 results on '"Randall T. Peterson"'
Search Results
2. Behavioral analysis through the lifespan of disc1 mutant zebrafish identifies defects in sensorimotor transformation
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Brock R. Pluimer, Devin L. Harrison, Chanon Boonyavairoje, Eric P. Prinssen, Mark Rogers-Evans, Randall T. Peterson, Summer B. Thyme, and Anjali K. Nath
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Behavior genetics ,Behavioral neuroscience ,Neuroscience ,Science - Abstract
Summary: DISC1 is a genetic risk factor for multiple psychiatric disorders. Compared to the dozens of murine Disc1 models, there is a paucity of zebrafish disc1 models—an organism amenable to high-throughput experimentation. We conducted the longitudinal neurobehavioral analysis of disc1 mutant zebrafish across key stages of life. During early developmental stages, disc1 mutants exhibited abrogated behavioral responses to sensory stimuli across multiple testing platforms. Moreover, during exposure to an acoustic sensory stimulus, loss of disc1 resulted in the abnormal activation of neurons in the pallium, cerebellum, and tectum—anatomical sites involved in the integration of sensory perception and motor control. In adulthood, disc1 mutants exhibited sexually dimorphic reduction in anxiogenic behavior in novel paradigms. Together, these findings implicate disc1 in sensorimotor processes and the genesis of anxiogenic behaviors, which could be exploited for the development of novel treatments in addition to investigating the biology of sensorimotor transformation in the context of disc1 deletion. more...
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- 2023
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Catalog
3. A zebrafish model of combined saposin deficiency identifies acid sphingomyelinase as a potential therapeutic target
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Tejia Zhang, Ivy Alonzo, Chris Stubben, Yijie Geng, Chelsea Herdman, Nancy Chandler, Kim P. Doane, Brock R. Pluimer, Sunia A. Trauger, and Randall T. Peterson
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lipidomics ,lysosomal storage disease ,zebrafish ,Medicine ,Pathology ,RB1-214 - Published
- 2023
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4. Glyoxylate protects against cyanide toxicity through metabolic modulation
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Jason R. Nielson, Anjali K. Nath, Kim P. Doane, Xu Shi, Jangwoen Lee, Emily G. Tippetts, Kusumika Saha, Jordan Morningstar, Kevin G. Hicks, Adriano Chan, Yanbin Zhao, Amy Kelly, Tara B. Hendry-Hofer, Alyssa Witeof, Patrick Y. Sips, Sari Mahon, Vikhyat S. Bebarta, Vincent Jo Davisson, Gerry R. Boss, Jared Rutter, Calum A. MacRae, Matthew Brenner, Robert E. Gerszten, and Randall T. Peterson more...
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Medicine ,Science - Abstract
Abstract Although cyanide’s biological effects are pleiotropic, its most obvious effects are as a metabolic poison. Cyanide potently inhibits cytochrome c oxidase and potentially other metabolic enzymes, thereby unleashing a cascade of metabolic perturbations that are believed to cause lethality. From systematic screens of human metabolites using a zebrafish model of cyanide toxicity, we have identified the TCA-derived small molecule glyoxylate as a potential cyanide countermeasure. Following cyanide exposure, treatment with glyoxylate in both mammalian and non-mammalian animal models confers resistance to cyanide toxicity with greater efficacy and faster kinetics than known cyanide scavengers. Glyoxylate-mediated cyanide resistance is accompanied by rapid pyruvate consumption without an accompanying increase in lactate concentration. Lactate dehydrogenase is required for this effect which distinguishes the mechanism of glyoxylate rescue as distinct from countermeasures based solely on chemical cyanide scavenging. Our metabolic data together support the hypothesis that glyoxylate confers survival at least in part by reversing the cyanide-induced redox imbalances in the cytosol and mitochondria. The data presented herein represent the identification of a potential cyanide countermeasure operating through a novel mechanism of metabolic modulation. more...
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- 2022
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5. An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency
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Kevin A. Hope, Alexys R. Berman, Randall T. Peterson, and Clement Y. Chow
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Genetics ,QH426-470 - Abstract
NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Exclusive dNGLY1 expression in serotonin and dopamine neurons, in an otherwise dNGLY1 deficient fly, was sufficient to partially rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119, lithium, and GSK3 knockdown. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects in dNGLY1 deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that is regulated by NGLY1 and regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease. Author summary NGLY1 deficiency is a rare disease with no effective treatment. We conducted a drug repurposing screen and used the Connectivity Map, a transcriptional-based computational approach, to identify compounds that may serve as therapeutics for NGLY1 deficient individuals. The drug repurposing screen identified FDA-approved compounds acting through the serotonin and dopamine pathway that partially rescued lethality in an NGLY1 deficiency fly model. We also found that expressing dNGLY1 (the Drosophila ortholog of NGLY1) exclusively in serotonin neurons, in an otherwise dNGLY1 deficient fly, partially rescued lethality. These data indicate the importance of the serotonin and dopamine systems in NGLY1 deficiency. The Connectivity Map analyses found GSK3 inhibitors as potential therapeutic compounds, which were validated in vivo in the fly. Furthermore, knockdown of sgg (the Drosophila ortholog of GSK3) partially rescued lethality in dNGLY1 deficient flies, suggesting GSK3 as a therapeutic target for NGLY1 deficiency. Taken together, this work identifies therapeutic strategies for NGLY1 deficiency. more...
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- 2022
6. Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation
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Matthew N. McCarroll, Leo Gendelev, Reid Kinser, Jack Taylor, Giancarlo Bruni, Douglas Myers-Turnbull, Cole Helsell, Amanda Carbajal, Capria Rinaldi, Hye Jin Kang, Jung Ho Gong, Jason K. Sello, Susumu Tomita, Randall T. Peterson, Michael J. Keiser, and David Kokel more...
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Science - Abstract
Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish. more...
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- 2019
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7. The zebrafish subcortical social brain as a model for studying social behavior disorders
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Yijie Geng and Randall T. Peterson
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Autism ,Phylogenetic conservation ,Model organism ,Social deficit ,Neuropsychiatric disorders ,Behavioral assay ,Medicine ,Pathology ,RB1-214 - Abstract
Social behaviors are essential for the survival and reproduction of social species. Many, if not most, neuropsychiatric disorders in humans are either associated with underlying social deficits or are accompanied by social dysfunctions. Traditionally, rodent models have been used to model these behavioral impairments. However, rodent assays are often difficult to scale up and adapt to high-throughput formats, which severely limits their use for systems-level science. In recent years, an increasing number of studies have used zebrafish (Danio rerio) as a model system to study social behavior. These studies have demonstrated clear potential in overcoming some of the limitations of rodent models. In this Review, we explore the evolutionary conservation of a subcortical social brain between teleosts and mammals as the biological basis for using zebrafish to model human social behavior disorders, while summarizing relevant experimental tools and assays. We then discuss the recent advances gleaned from zebrafish social behavior assays, the applications of these assays to studying related disorders, and the opportunities and challenges that lie ahead. more...
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- 2019
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8. Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma
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Haley R. Noonan, Ana M. Metelo, Caramai N. Kamei, Randall T. Peterson, Iain A. Drummond, and Othon Iliopoulos
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VHL disease ,HIF2a ,Renal cell carcinoma ,Zebrafish cancer model ,Pronephros ,Medicine ,Pathology ,RB1-214 - Abstract
Patients with von Hippel–Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. ‘Clear cell’ tumors contain large, proliferating cells with ‘clear cytoplasm’, and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis. A zebrafish model with a homozygous inactivation in the VHL gene (vhl−/−) recapitulates several aspects of the human disease, including development of highly vascular lesions in the brain and the retina and erythrocytosis. Here, we characterize for the first time the epithelial abnormalities present in the kidney of the vhl−/− zebrafish larvae as a first step in building a model of ccRCC in zebrafish. Our data show that the vhl−/− zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis. This phenotype of the vhl−/− pronephros is reminiscent of clear cell histology, indicating that the vhl−/− mutant zebrafish might serve as a model of early stage RCC. Treatment of vhl−/− zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC. more...
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- 2016
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9. A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed
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Rahul Palchaudhuri, Michael J. Lambrecht, Rachel C. Botham, Kathryn C. Partlow, Tjakko J. van Ham, Karson S. Putt, Laurie T. Nguyen, Seok-Ho Kim, Randall T. Peterson, Timothy M. Fan, and Paul J. Hergenrother more...
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Biology (General) ,QH301-705.5 - Abstract
Apoptosis is generally believed to be a process that requires several hours, in contrast to non-programmed forms of cell death that can occur in minutes. Our findings challenge the time-consuming nature of apoptosis as we describe the discovery and characterization of a small molecule, named Raptinal, which initiates intrinsic pathway caspase-dependent apoptosis within minutes in multiple cell lines. Comparison to a mechanistically diverse panel of apoptotic stimuli reveals that Raptinal-induced apoptosis proceeds with unparalleled speed. The rapid phenotype enabled identification of the critical roles of mitochondrial voltage-dependent anion channel function, mitochondrial membrane potential/coupled respiration, and mitochondrial complex I, III, and IV function for apoptosis induction. Use of Raptinal in whole organisms demonstrates its utility for studying apoptosis in vivo for a variety of applications. Overall, rapid inducers of apoptosis are powerful tools that will be used in a variety of settings to generate further insight into the apoptotic machinery. more...
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- 2015
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10. PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation
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Anjali K. Nath, Justine H. Ryu, Youngnam N. Jin, Lee D. Roberts, Andre Dejam, Robert E. Gerszten, and Randall T. Peterson
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Biology (General) ,QH301-705.5 - Abstract
Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1 and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration. more...
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- 2015
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11. The zebrafish as a tool to identify novel therapies for human cardiovascular disease
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Aarti Asnani and Randall T. Peterson
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Cardiovascular ,Drug discovery ,Zebrafish ,Medicine ,Pathology ,RB1-214 - Abstract
Over the past decade, the zebrafish has become an increasingly popular animal model for the study of human cardiovascular disease. Because zebrafish embryos are transparent and their genetic manipulation is straightforward, the zebrafish has been used to recapitulate a number of cardiovascular disease processes ranging from congenital heart defects to arrhythmia to cardiomyopathy. The use of fluorescent reporters has been essential to identify two discrete phases of cardiomyocyte differentiation necessary for normal cardiac development in the zebrafish. These phases are analogous to the differentiation of the two progenitor heart cell populations in mammals, termed the first and second heart fields. The small size of zebrafish embryos has enabled high-throughput chemical screening to identify small-molecule suppressors of fundamental pathways in vasculogenesis, such as the BMP axis, as well as of common vascular defects, such as aortic coarctation. The optical clarity of zebrafish has facilitated studies of valvulogenesis as well as detailed electrophysiological mapping to characterize the early cardiac conduction system. One unique aspect of zebrafish larvae is their ability to oxygenate through diffusion alone, permitting the study of mutations that cause severe cardiomyopathy phenotypes such as silent heart and pickwickm171, which mimic titin mutations observed in human dilated cardiomyopathy. Above all, the regenerative capacity of zebrafish presents a particularly exciting opportunity to discover new therapies for cardiac injury, including scar formation following myocardial infarction. This Review will summarize the current state of the field and describe future directions to advance our understanding of human cardiovascular disease. more...
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- 2014
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12. A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12
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Alexa Burger, Aleksandr Vasilyev, Ritu Tomar, Martin K. Selig, G. Petur Nielsen, Randall T. Peterson, Iain A. Drummond, and Daniel A. Haber
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HRASV12 ,Cancer ,Chordoma ,Drug treatment ,Rapamycin ,Zebrafish ,Medicine ,Pathology ,RB1-214 - Abstract
Chordoma is a malignant tumor thought to arise from remnants of the embryonic notochord, with its origin in the bones of the axial skeleton. Surgical resection is the standard treatment, usually in combination with radiation therapy, but neither chemotherapeutic nor targeted therapeutic approaches have demonstrated success. No animal model and only few chordoma cell lines are available for preclinical drug testing, and, although no druggable genetic drivers have been identified, activation of EGFR and downstream AKT-PI3K pathways have been described. Here, we report a zebrafish model of chordoma, based on stable transgene-driven expression of HRASV12 in notochord cells during development. Extensive intra-notochordal tumor formation is evident within days of transgene expression, ultimately leading to larval death. The zebrafish tumors share characteristics of human chordoma as demonstrated by immunohistochemistry and electron microscopy. The mTORC1 inhibitor rapamycin, which has some demonstrated activity in a chordoma cell line, delays the onset of tumor formation in our zebrafish model, and improves survival of tumor-bearing fish. Consequently, the HRASV12-driven zebrafish model of chordoma could enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer. more...
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- 2014
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13. Intravital correlated microscopy reveals differential macrophage and microglial dynamics during resolution of neuroinflammation
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Tjakko J. van Ham, Colleen A. Brady, Ruby D. Kalicharan, Nynke Oosterhof, Jeroen Kuipers, Anneke Veenstra-Algra, Klaas A. Sjollema, Randall T. Peterson, Harm H. Kampinga, and Ben N. G. Giepmans
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Brain ,Intravital microscopy ,Leukocytes ,Microglia ,Neurodegeneration ,Zebrafish ,Medicine ,Pathology ,RB1-214 - Abstract
Many brain diseases involve activation of resident and peripheral immune cells to clear damaged and dying neurons. Which immune cells respond in what way to cues related to brain disease, however, remains poorly understood. To elucidate these in vivo immunological events in response to brain cell death we used genetically targeted cell ablation in zebrafish. Using intravital microscopy and large-scale electron microscopy, we defined the kinetics and nature of immune responses immediately following injury. Initially, clearance of dead cells occurs by mononuclear phagocytes, including resident microglia and macrophages of peripheral origin, whereas amoeboid microglia are exclusively involved at a later stage. Granulocytes, on the other hand, do not migrate towards the injury. Remarkably, following clearance, phagocyte numbers decrease, partly by phagocyte cell death and subsequent engulfment of phagocyte corpses by microglia. Here, we identify differential temporal involvement of microglia and peripheral macrophages in clearance of dead cells in the brain, revealing the chronological sequence of events in neuroinflammatory resolution. Remarkably, recruited phagocytes undergo cell death and are engulfed by microglia. Because adult zebrafish treated at the larval stage lack signs of pathology, it is likely that this mode of resolving immune responses in brain contributes to full tissue recovery. Therefore, these findings suggest that control of such immune cell behavior could benefit recovery from neuronal damage. more...
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- 2014
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14. Zebrafish as a Mainstream Model for In Vivo Systems Pharmacology and Toxicology
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Calum A, MacRae and Randall T, Peterson
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Pharmacology ,Toxicology - Abstract
Pharmacology and toxicology are part of a much broader effort to understand the relationship between chemistry and biology. While biomedicine has necessarily focused on specific cases, typically of direct human relevance, there are real advantages in pursuing more systematic approaches to characterizing how health and disease are influenced by small molecules and other interventions. In this context, the zebrafish is now established as the representative screenable vertebrate and, through ongoing advances in the available scale of genome editing and automated phenotyping, is beginning to address systems-level solutions to some biomedical problems. The addition of broader efforts to integrate information content across preclinical model organisms and the incorporation of rigorous analytics, including closed-loop deep learning, will facilitate efforts to create systems pharmacology and toxicology with the ability to continuously optimize chemical biological interactions around societal needs. In this review, we outline progress toward this goal. Expected final online publication date for the more...
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- 2023
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15. Rapid Mounting of Zebrafish Larvae for Brain Imaging
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Yijie Geng and Randall T. Peterson
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animal structures ,genetic structures ,Larva ,parasitic diseases ,fungi ,Animals ,Brain ,Neuroimaging ,Animal Science and Zoology ,TechnoFish ,human activities ,Zebrafish ,Developmental Biology - Abstract
Brain imaging requires mounting of zebrafish larvae in a vertical position, but anesthetized or fixed larvae tend to fall on their sides without external support. Current solution is to manually hold individual larva until liquid agarose solidifies, which is time consuming, labor intensive, and unfriendly to beginners. We developed a method to form larva-shaped slots in agarose gel using a computer numerical controlled manufactured mold. Each slot nearly perfectly fits a larva in its upright position, and larvae can be easily mounted by inserting into the slots. On average, each larva can be mounted in more...
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- 2021
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16. MIC-Drop: A platform for large-scale in vivo CRISPR screens
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Calum A. MacRae, Korak Chakraborti, H. Joseph Yost, Zachary P. Harmer, Manu Beerens, Jing-Ruey J. Yeh, Chelsea Herdman, Randall T. Peterson, and Saba Parvez
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Multidisciplinary ,biology ,ved/biology ,ved/biology.organism_classification_rank.species ,Mutant ,Cell Culture Techniques ,High-Throughput Nucleotide Sequencing ,Computational biology ,Microfluidic Analytical Techniques ,biology.organism_classification ,Cardiovascular System ,Article ,Animals ,CRISPR ,Genetic Testing ,CRISPR-Cas Systems ,Model organism ,Gene ,Zebrafish ,Function (biology) ,Ribonucleoprotein ,Genetic screen - Abstract
Screen time for CRISPR CRISPR-Cas9 has been used to edit the genomes of organisms ranging from fruit flies to primates, but it has not been used in large-scale genetic screens in animals because generating, validating, and keeping track of large numbers of mutant animals is prohibitively laborious. Parvez et al . have developed Multiplexed Intermixed CRISPR Droplets, or MIC-Drop, a platform combining droplet microfluidics, en masse CRISPR injections, and barcoding, to enable large-scale genetic screens. In pilot phenotypic screens in zebrafish, MIC-Drop enabled rapid identification of the target of a small molecule and discovery of several new genes governing cardiovascular development. MIC-Drop is potentially scalable to thousands of targets and adaptable to diverse organisms and experiments. —DJ more...
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- 2021
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17. Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles
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Hannah J. Eckvahl, Dennis Svatunek, Raphael M. Franzini, Brian J. Levandowski, Saba Parvez, Albert C. Liu, Julian Tu, Kendall N. Houk, and Randall T. Peterson
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Steric effects ,Tetrazoles ,Alkenes ,010402 general chemistry ,01 natural sciences ,London dispersion force ,Article ,Catalysis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Tetrazine ,Nitriles ,Animals ,Chemoselectivity ,Zebrafish ,Fluorescent Dyes ,Bioconjugation ,Cycloaddition Reaction ,010405 organic chemistry ,Optical Imaging ,Serum Albumin, Bovine ,General Medicine ,General Chemistry ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,chemistry ,Alkynes ,Functional group ,Cattle ,Bioorthogonal chemistry - Abstract
Bioorthogonal reactions are of great value in the life sciences. The isocyano group is a structurally compact bioorthogonal functional group that reacts with tetrazines under physiological conditions. Here we report that bulky tetrazine substituents accelerate this cycloaddition. Computational studies suggest that dispersion forces between the isocyano group and the tetrazine substituents in the transition state contribute to the atypical structure-activity relationship. Stable asymmetric tetrazines that react with isonitriles at rate constants as high as 57 M(−1)s(−1) were accessible by combining bulky and electron-withdrawing substituents. Sterically encumbered tetrazines react selectively with isonitriles in the presence of strained alkenes/alkynes, which allows for the orthogonal labeling of three proteins. The established principles will open new opportunities for developing tetrazine reactants with improved characteristics for diverse labeling and release applications with isonitriles. more...
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- 2019
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18. Developing zebrafish disease models for in vivo small molecule screens
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Pui-ying Lam and Randall T. Peterson
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0301 basic medicine ,animal structures ,ved/biology.organism_classification_rank.species ,Drug Evaluation, Preclinical ,Mutagenesis (molecular biology technique) ,Disease ,Computational biology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Analytical Chemistry ,03 medical and health sciences ,In vivo ,Animals ,Humans ,Regeneration ,Model organism ,Zebrafish ,Wound Healing ,biology ,ved/biology ,Regeneration (biology) ,fungi ,biology.organism_classification ,Small molecule ,In vitro ,High-Throughput Screening Assays ,0104 chemical sciences ,Disease Models, Animal ,030104 developmental biology ,Mutagenesis ,embryonic structures - Abstract
The zebrafish is a model organism that allows in vivo studies to be performed at a scale usually restricted to in vitro studies. As such, the zebrafish is well suited to in vivo screens, in which thousands of small molecules are tested for their ability to modify disease phenotypes in zebrafish disease models. Numerous approaches have been developed for modeling human diseases in zebrafish, including mutagenesis, transgenesis, pharmacological approaches, wounding, and exposure to infectious or cancerous agents. We review the various strategies for modeling human diseases in zebrafish and discuss important considerations when developing zebrafish models for use in in vivo small molecule screens. more...
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- 2019
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19. Intramuscular administration of hexachloroplatinate reverses cyanide-induced metabolic derangements and counteracts severe cyanide poisoning
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Robert E. Gerszten, Jangwoen Lee, Vikhyat S. Bebarta, Tara B. Hendry-Hofer, Gregg Knipp, Alyssa E. Witeof, Matthew Brenner, Calum A. MacRae, Sari B. Mahon, L. Tiffany Lyle, Randall T. Peterson, Gerry R. Boss, Vincent Jo Davisson, Anjali K. Nath, and Jordan Morningstar more...
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0301 basic medicine ,Cancer Research ,Physiology ,Smoke inhalation ,Cyanide ,medicine.medical_treatment ,Pharmacology ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Article ,010309 optics ,03 medical and health sciences ,chemistry.chemical_compound ,Pharmacokinetics ,0103 physical sciences ,medicine ,Antidote ,medicine.disease ,3. Good health ,Bioavailability ,030104 developmental biology ,chemistry ,Toxicity ,Molecular Medicine ,Cyanide poisoning ,Hexachloroplatinate - Abstract
Cyanide is a highly toxic industrial chemical that is widely used by manufactures. Smoke inhalation during household fires is the most common source of cyanide poisoning while additional risks to civilians include industrial accidents and terrorist attacks. Despite the risks to large numbers of individuals, an antidote capable of administration at scale adequate for a mass casualty, prehospital scenario does not yet exist. Previously, we demonstrated that intravenous cisplatin analogues accelerate recovery from cyanide poisoning in mice and rabbits. Of the dozens of platinum-based organometallic complexes tested, hexachloroplatinate (HCP) emerged as a promising lead compound, exhibiting strong affinity for cyanide and efficacy across model systems. Here, we show HCP is an antidote to lethal cyanide exposure and importantly is effective when delivered intramuscularly. The pharmacokinetic profile of HCP exhibited bioavailability in the systemic circulation 2.5 minutes post-treatment and subsequent renal clearance of HCP-cyanide. HCP restored parameters of cellular physiology including cytochrome oxidase redox state and TCA cycle metabolism. We next validated these findings in a large animal model (swine). Finally, preclinical safety studies in mice revealed minimal toxicity. Cumulatively, these findings demonstrate hexachloroplatinate is a promising lead compound for development of an intramuscular injectable cyanide antidote for mass casualty scenarios. more...
- Published
- 2018
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20. Cyp1 Inhibition Prevents Doxorubicin‐Induced Cardiomyopathy in a Zebrafish Heart‐Failure Model
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Jason E. Imbriglio, Christine Andrews, Rajan Anand, Hugo Padilla, Dann L. Parker, Manu Beerens, Anita Vohra, Pui-ying Lam, Ivan Cornella Taracido, Peter S. Kutchukian, Aarti Asnani, Sarah Lane, Randall T. Peterson, John P. Caldwell, Douglas G. Johns, Steve Sorota, and Calum A. MacRae more...
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medicine.medical_treatment ,Cardiomyopathy ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Animals, Genetically Modified ,Small Molecule Libraries ,Structure-Activity Relationship ,medicine ,Animals ,Doxorubicin ,Zebrafish ,Cytochrome P450 Family 1 ,Molecular Biology ,Cardioprotection ,Heart Failure ,Chemotherapy ,Cardiotoxicity ,biology ,010405 organic chemistry ,business.industry ,Drug discovery ,Organic Chemistry ,Zebrafish Proteins ,medicine.disease ,biology.organism_classification ,0104 chemical sciences ,Disease Models, Animal ,Phenotype ,Mutagenesis ,Heart failure ,Molecular Medicine ,business ,Cardiomyopathies ,medicine.drug - Abstract
Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, we previously established a zebrafish model of doxorubicin-induced cardiomyopathy for small molecule screening. Using this model, we previously identified several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish as well as in mouse models. In this study, we have expanded our exploration of doxorubicin cardiotoxicity by screening 2,271 small molecules from a proprietary, target-annotated tool compound collection. We found 120 small molecules that can prevent doxorubicin-induced cardiotoxicity, including seven highly-effective compounds. Of these, all seven exhibited inhibitory activity towards Cytochrome P450 family 1 (CYP1). These results are consistent with our previous findings in which visnagin, a CYP1 inhibitor, also prevented doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection. more...
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- 2020
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21. Engineered CRISPR-Cas9 nucleases with altered PAM specificities
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Benjamin P. Kleinstiver, Michelle S. Prew, Shengdar Q. Tsai, Ved V. Topkar, Nhu T. Nguyen, Zongli Zheng, Andrew P. W. Gonzales, Zhuyun Li, Randall T. Peterson, Jing-Ruey Joanna Yeh, Martin J. Aryee, and J. Keith Joung more...
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Staphylococcus aureus ,Streptococcus pyogenes ,CRISPR-Associated Proteins ,Computational biology ,Biology ,Protein Engineering ,medicine.disease_cause ,Genome ,Article ,Cell Line ,Substrate Specificity ,Molecular engineering ,stomatognathic system ,parasitic diseases ,medicine ,Animals ,Humans ,Streptococcus thermophilus ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Nucleotide Motifs ,Zebrafish ,Epigenomics ,Genetics ,Mutation ,Multidisciplinary ,Protein engineering ,Protospacer adjacent motif ,Genomic engineering ,Amino Acid Substitution ,CRISPR-Cas Systems ,Directed Molecular Evolution - Abstract
Although CRISPR-Cas9 nucleases are widely used for genome editing1, 2, the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM)3–6. As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-Seq analysis7. In addition, we identified and characterized another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGA PAMs and/or mismatched spacers. We also found that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities. more...
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- 2015
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22. Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides
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Richard B. Westkaemper, Andrew J. Rennekamp, Vsevolod Katritch, Eyal Vardy, Bryan L. Roth, Craig W. Stevens, Philip D. Mosier, Raymond C. Stevens, Wesley K. Kroeze, Randall T. Peterson, and Maria F. Sassano more...
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Amphibian ,Molecular Sequence Data ,Clinical Biochemistry ,Molecular Dynamics Simulation ,Biochemistry ,Article ,Amphibians ,chemistry.chemical_compound ,Species Specificity ,biology.animal ,Drug Discovery ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Opioid peptide ,Peptide sequence ,Molecular Biology ,Zebrafish ,Skin ,Pharmacology ,Binding Sites ,biology ,Behavior, Animal ,Lamprey ,General Medicine ,Dermorphin ,biology.organism_classification ,Protein Structure, Tertiary ,Analgesics, Opioid ,Kinetics ,chemistry ,Opioid Peptides ,Deltorphin ,Receptors, Opioid ,Molecular Medicine ,Leucine ,Peptides ,Oligopeptides ,Sequence Alignment - Abstract
It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here we test this idea comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. Interestingly, the insensitivity of the delta opioid receptor (DOR) to deltorphin was due to variation of a single amino acid– Trp7.35—which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish and amphibians. The deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides. more...
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- 2015
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23. Bonnevillamides, Linear Heptapeptides Isolated from a Great Salt Lake-Derived Streptomyces sp
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Jaclyn M. Winter, Randall T. Peterson, Jason R. Nielson, and Guangwei Wu
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0301 basic medicine ,Models, Molecular ,Embryo, Nonmammalian ,Stereochemistry ,Heart growth ,Electrospray ionization ,Pharmaceutical Science ,01 natural sciences ,Streptomyces ,Great Salt Lake ,hypersaline environment ,heptapeptide ,azetidine ,Streptomyces sp ,zebrafish ,Article ,03 medical and health sciences ,Residue (chemistry) ,Utah ,Drug Discovery ,Animals ,Proline ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,chemistry.chemical_classification ,Proteinogenic amino acid ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Absolute configuration ,biology.organism_classification ,0104 chemical sciences ,Amino acid ,Lakes ,030104 developmental biology ,chemistry ,Larva ,Peptides - Abstract
Streptomyces sp. GSL-6B was isolated from sediment collected from the Great Salt Lake and investigation of its organic extract led to the isolation of three new linear heptapeptides, bonnevillamides A (1), B (2), and C (3). The bonnevillamides represent a new class of linear peptides featuring unprecedented non-proteinogenic amino acids. All three peptides contain the newly characterized bonnevillic acid moiety (3-(3,5-dichloro-4-methoxyphenyl)-2-hydroxyacrylic acid), as well as a heavily modified proline residue. Moreover, in bonnevillamide A, the terminal proline residue found in bonnevillamides B and C is replaced with 4-methyl-azetidine-2-carboxylic acid methyl ester. The structures of the three heptapeptides were elucidated by NMR, high-resolution electrospray ionization mass spectroscopy (HRESIMS), and LC-MS/MS, and the absolute configuration of all proteinogenic amino acid residues were determined by advanced Marfey’s method. Bonnevillamides A, B and C were evaluated for their effects on zebrafish embryo development. All three heptapeptides were shown to modulate heart growth and cardiac function, with bonnevillamide B having the most pronounced effect. more...
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- 2017
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24. Methods for targeted mutagenesis in zebrafish using TALENs
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Jing-Ruey J. Yeh, Woong Y. Hwang, and Randall T. Peterson
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Genetics ,Transcription activator-like effector nuclease ,Deoxyribonucleases ,biology ,Gene targeting ,Protein engineering ,Protein Engineering ,biology.organism_classification ,Article ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,Genome engineering ,chemistry.chemical_compound ,Restriction enzyme ,chemistry ,Mutagenesis, Site-Directed ,Animals ,Molecular Biology ,Zebrafish ,DNA - Abstract
The transcription activator-like effector (TALE) nucleases, or TALENs, are customizable restriction enzymes that may be used to induce mutations at nearly any investigator-specified DNA sequence in zebrafish. The DNA-binding specificities of TALENs are determined by a protein array comprised of four types of TALE repeats, where each repeat recognizes a different DNA base. Here, we describe methods for constructing TALEN vectors that have been shown to achieve high success rates and mutation efficiencies in zebrafish. In addition, we discuss simple techniques and protocols that can be used to detect TALEN-induced mutations at almost any genomic locus. These methods should enable zebrafish researchers to quickly generate targeted mutations at their genes-of-interest. more...
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- 2014
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25. Back Cover: Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles (Angew. Chem. Int. Ed. 27/2019)
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Kendall N. Houk, Julian Tu, Dennis Svatunek, Saba Parvez, Brian J. Levandowski, Randall T. Peterson, Hannah J. Eckvahl, Raphael M. Franzini, and Albert C. Liu
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Bioconjugation ,Chemistry ,Computational chemistry ,Cover (algebra) ,General Chemistry ,Bioorthogonal chemistry ,Chemoselectivity ,London dispersion force ,Catalysis ,Cycloaddition - Published
- 2019
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26. Rücktitelbild: Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles (Angew. Chem. 27/2019)
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Dennis Svatunek, Saba Parvez, Brian J. Levandowski, Julian Tu, Randall T. Peterson, Raphael M. Franzini, Albert C. Liu, Hannah J. Eckvahl, and Kendall N. Houk
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Computational chemistry ,Chemistry ,General Medicine ,London dispersion force ,Cycloaddition - Published
- 2019
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27. Effects of Vascular-Endothelial Protein Tyrosine Phosphatase Inhibition on Breast Cancer Vasculature and Metastatic Progression
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Brian P. Walcott, Nathaniel D. Kirkpatrick, Cristina T. Kesler, Dan G. Duda, Benjamin J. Vakoc, Rakesh K. Jain, Matija Snuderl, Dai Fukumura, Timothy P. Padera, Nisha Gupta, Rekha Samuel, John Yazbek, Eleanor I Ager, Shuhan Wang, Randall T. Peterson, Takahiro Heishi, Shom Goel, John D. Martin, and Yuhui Huang more...
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Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Nitric Oxide Synthase Type III ,Endothelium ,Angiogenesis ,Angiogenesis Inhibitors ,Antineoplastic Agents ,Breast Neoplasms ,Protein tyrosine phosphatase ,Biology ,Receptor tyrosine kinase ,Angiopoietin ,Mice ,Internal medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Enzyme Inhibitors ,Zebrafish ,Sprouting angiogenesis ,Neovascularization, Pathologic ,Tumor hypoxia ,Receptor-Like Protein Tyrosine Phosphatases, Class 3 ,Drug Synergism ,Zebrafish Proteins ,Receptor, TIE-2 ,Xenograft Model Antitumor Assays ,Enzyme Activation ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Disease Progression ,cardiovascular system ,Cancer research ,biology.protein ,Female - Abstract
Unlike blood vessels in healthy tissue, the solid tumor microvasculature is dysfunctional and immature. Tumor vessels harbor structural and functional instability, which facilitates several distinct stages of tumor progression, including early sprouting angiogenesis, metastatic cell extravasation into distant organs, and the development of established tumor hypoxia, which fuels metastasis and impairs the efficacy of antitumor therapies (1–9). The endothelial cell (EC) receptor tyrosine kinase Tie-2/Tek is a critical regulator of vascular maturity. Tie-2 activation by its agonistic ligand angiopoietin 1 (Ang-1) increases perivascular cell (PVC) coverage, tightens EC junctions, reduces permeability, and increases vessel diameter (10–12). Angiopoeitin-2 (Ang-2) antagonizes the effects of Ang-1 in a context-dependent manner (6). Recent studies have shown a deleterious role for Ang-2 in mediating tumor vessel abnormalities and metastasis (13,14), suggesting that Tie-2 deactivation by Ang-2 in part mediates the unstable vessel phenotype seen within tumors. Current strategies targeting the Ang/Tie-2 axis in tumors have focused primarily on direct targeting of the angiopoietins, but such studies have not directly examined complex context-dependent interactions between Ang-1 and Ang-2 or the effects of angiopoietin blockade on Tie-2 activity (15–18). There are currently 10 agents targeting the Ang/Tie-2 axis under investigation in clinical trials (19). Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an EC-specific receptor tyrosine phosphatase that dephosphorylates and consequently inactivates Tie-2 (20). The role of VE-PTP in the tumor vasculature is unknown. Recently, AKB-9778 has been developed as a novel, potent, and selective inhibitor of VE-PTP through structural modifications of 1,2,3,4-tetrahydroisoquinolinyl sulfamic acids (21). We hypothesized that pharmacological VE-PTP inhibition would activate Tie-2 signaling in ECs independent of Ang-1/Ang-2 ligands, stabilizing tumor vessels and mitigating the negative consequences of tumor vessel instability (20). more...
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- 2013
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28. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway
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Justin C. Wheat, Amir T. Fathi, David A. Sweetser, Andrew L. Kung, Randall T. Peterson, Jianfeng Wang, Jing-Ruey J. Yeh, Hossein Sadrzadeh, Xi Chen, Shan Jin, and Yiyun Zhang
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Myeloid ,Oncogene Proteins, Fusion ,Transplantation, Heterologous ,Immunology ,Mice, Transgenic ,Biology ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Mice ,RUNX1 Translocation Partner 1 Protein ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Cyclooxygenase Inhibitors ,Progenitor cell ,neoplasms ,Zebrafish ,beta Catenin ,Cell Proliferation ,Sulfonamides ,Myeloid Neoplasia ,Gene Expression Regulation, Leukemic ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,medicine.disease ,Embryonic stem cell ,Molecular biology ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,Cyclooxygenase 2 ,Core Binding Factor Alpha 2 Subunit ,Neoplastic Stem Cells ,Cancer research ,Bone marrow ,Stem cell ,K562 Cells ,Neoplasm Transplantation ,Signal Transduction ,K562 cells - Abstract
Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments. more...
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- 2013
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29. Induced and Sustained Hypernatremia for the Prevention and Treatment of Cerebral Edema Following Brain Injury
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Justine H. Ryu, Brian V. Nahed, Jean-Valery Coumans, Brian P. Walcott, Kristopher T. Kahle, Sameer A. Sheth, J. Marc Simard, and Randall T. Peterson
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Saline Solution, Hypertonic ,medicine.medical_specialty ,Hypernatremia ,Neurology ,Intracranial Pressure ,business.industry ,Traumatic brain injury ,Brain Edema ,Critical Care and Intensive Care Medicine ,medicine.disease ,Cerebral edema ,Hypertonic saline ,Bolus (medicine) ,Brain Injuries ,Anesthesia ,medicine ,Humans ,Neurology (clinical) ,business ,Hyponatremia ,Intracranial pressure - Abstract
Cerebral edema develops in response to and as a result of a variety of neurologic insults such as ischemic stroke, traumatic brain injury, and tumor. It deforms brain tissue, resulting in localized mass effect and increase in intracranial pressure (ICP) that are associated with a high rate of morbidity and mortality. When administered in bolus form, hyperosmolar agents such as mannitol and hypertonic saline have been shown to reduce total brain water content and decrease ICP, and are currently the mainstays of pharmacological treatment. However, surprisingly, little is known about the increasingly common clinical practice of inducing a state of sustained hypernatremia. Herein, we review the available studies employing sustained hyperosmolar therapy to induce hypernatremia for the prevention and/or treatment of cerebral edema. Insufficient evidence exists to recommend pharmacologic induction of hypernatremia as a treatment for cerebral edema. The strategy of vigilant avoidance of hyponatremia is currently a safer, potentially more efficacious paradigm. more...
- Published
- 2013
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30. Changing the scale and efficiency of chemical warfare countermeasure discovery using the zebrafish
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Calum A. MacRae and Randall T. Peterson
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Chemical Warfare Agents ,biology ,Operations research ,Scope (project management) ,Computer science ,Scale (chemistry) ,biology.organism_classification ,Article ,Chemical warfare ,Countermeasure ,Risk analysis (engineering) ,Drug Discovery ,Molecular Medicine ,Zebrafish - Abstract
As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approach that has been pioneered in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the establishment of a zebrafish platform for countermeasure discovery would offer a rapid response system for the development of antidotes to the continuous stream of new potential chemical warfare agents. more...
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- 2013
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31. A countermeasure development pipeline
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Calum A, MacRae, Gerry, Boss, Matthew, Brenner, Robert E, Gerszten, Sari, Mahon, and Randall T, Peterson
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Biomedical Research ,Cyanides ,National Institutes of Health (U.S.) ,Drug Discovery ,Animals ,Humans ,Metabolomics ,Program Development ,United States ,Article - Abstract
We have developed an integrated pipeline for countermeasure discovery that, under the auspices of the National Institutes of Health Countermeasures Against Chemical Threats network, is one of the few efforts within academia that by design spans the spectrum from discovery to phase I. The successful implementation of this approach for cyanide would enable efficient proof-of-concept studies that would lay the foundation for a generalizable strategy for parallel mechanistic studies and accelerated countermeasure development in the face of new and emerging chemical threats. more...
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- 2016
32. Highly efficient generation of heritable zebrafish gene mutations using homo- and heterodimeric TALENs
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Jeffry D. Sander, J. Keith Joung, Cyd Khayter, Woong Y. Hwang, Lindsay Cade, Deepak Reyon, Shengdar Q. Tsai, Jing-Ruey J. Yeh, Randall T. Peterson, and Samir Patel
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Molecular Sequence Data ,ved/biology.organism_classification_rank.species ,Gene mutation ,Biology ,Germline ,Gene Knockout Techniques ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Animals ,Deoxyribonucleases, Type II Site-Specific ,Model organism ,Gene ,Zebrafish ,Alleles ,030304 developmental biology ,0303 health sciences ,Transcription activator-like effector nuclease ,Base Sequence ,Nucleic Acid Enzymes ,ved/biology ,Effector ,biology.organism_classification ,DNA-Binding Proteins ,Mutagenesis ,Mutation ,Trans-Activators ,Dimerization ,030217 neurology & neurosurgery - Abstract
Transcription activator-like effector nucleases (TALENs) are powerful new research tools that enable targeted gene disruption in a wide variety of model organisms. Recent work has shown that TALENs can induce mutations in endogenous zebrafish genes, but to date only four genes have been altered, and larger-scale tests of the success rate, mutation efficiencies and germline transmission rates have not been described. Here, we constructed homodimeric TALENs to 10 different targets in various endogenous zebrafish genes and found that 7 nuclease pairs induced targeted indel mutations with high efficiencies ranging from 2 to 76%. We also tested obligate heterodimeric TALENs and found that these nucleases induce mutations with comparable or higher frequencies and have better toxicity profiles than their homodimeric counterparts. Importantly, mutations induced by both homodimeric and heterodimeric TALENs are passed efficiently through the germline, in some cases reaching 100% transmission. For one target gene sequence, we observed substantially reduced mutagenesis efficiency for a variant site bearing two mismatched nucleotides, raising the possibility that TALENs might be used to perform allele-specific gene disruption. Our results suggest that construction of one to two heterodimeric TALEN pairs for any given gene will, in most cases, enable researchers to rapidly generate knockout zebrafish. more...
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- 2012
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33. Systematic Approaches to Toxicology in the Zebrafish
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Calum A. MacRae and Randall T. Peterson
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Carcinogenicity Tests ,Toxicogenetics ,Drug Evaluation, Preclinical ,Genomics ,Toxicology ,Toxicology studies ,Drug Delivery Systems ,Drug Discovery ,Toxicity Tests ,Animals ,Pharmacokinetics ,Carcinogenicity Test ,Zebrafish ,Neurons ,Pharmacology ,biology ,Extramural ,Drug discovery ,Muscles ,fungi ,Heart ,biology.organism_classification ,Gastrointestinal Tract ,Phenotype ,Liver ,Pharmaceutical Preparations ,Drug development ,Drug Design ,Models, Animal - Abstract
As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology. more...
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- 2012
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34. Rapid behavior—based identification of neuroactive small molecules in the zebrafish
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Andreas A. Werdich, Stephen J. Haggarty, Sonia Kim, Rita Mateus, Brian K. Shoichet, David Kokel, Randall T. Peterson, Rick White, Christian Laggner, Calum A. MacRae, Jennifer Bryan, Chung Yan J Cheung, and David Healey more...
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Genetics ,0303 health sciences ,Drug discovery ,Cell Biology ,Computational biology ,Biology ,biology.organism_classification ,Small molecule ,Article ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Molecular targets ,Identification (biology) ,Molecular Biology ,Zebrafish ,030217 neurology & neurosurgery ,Function (biology) ,030304 developmental biology - Abstract
Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. more...
- Published
- 2010
35. Drug-Sensitized Zebrafish Screen Identifies Multiple Genes, Including GINS3 , as Regulators of Myocardial Repolarization
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Aravinda Chakravarti, Adam Amsterdam, Albert M. Kim, A. Pfeufer, Dan M. Roden, David S. Rosenbaum, Jeffrey R. Winterfield, John D. Mably, Khaled M. Sabeh, Serena Sanna, Stefan Kääb, Calum A. MacRae, David J. Milan, Randall T. Peterson, Dan E. Arking, and Ian L. Jones more...
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medicine.medical_specialty ,Long QT syndrome ,Bioinformatics ,Sudden death ,Article ,Membrane Potentials ,Sudden cardiac death ,Heart Conduction System ,Risk Factors ,Physiology (medical) ,Internal medicine ,Genes, Regulator ,medicine ,Animals ,Humans ,Repolarization ,Myocytes, Cardiac ,Zebrafish ,biology ,business.industry ,Gene Expression Profiling ,Heart ,medicine.disease ,biology.organism_classification ,Gene expression profiling ,Long QT Syndrome ,Death, Sudden, Cardiac ,Phenotype ,Models, Animal ,Cardiology ,Electrical conduction system of the heart ,Cardiology and Cardiovascular Medicine ,business ,Genetic screen - Abstract
Background— Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. Although genetic studies of familial long-QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals. Methods and Results— We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3 , that affect cardiac repolarization. Testing these genes for human relevance in 2 concurrently completed genome-wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus, which is strongly associated with QT interval. Conclusions— This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3 , the human ortholog of which is a major locus in 2 concurrent human genome-wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization. more...
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- 2009
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36. Systematizing Serendipity for Cardiovascular Drug Discovery
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Peter J. Schlueter and Randall T. Peterson
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High rate ,Drug ,Drug discovery ,business.industry ,Serendipity ,media_common.quotation_subject ,Disease mechanisms ,Cardiovascular Agents ,Disease ,Computational biology ,Pharmacology ,Article ,Physiology (medical) ,Drug Discovery ,Cardiovascular agent ,Animals ,Humans ,Medicine ,Cardiovascular drug ,Cardiology and Cardiovascular Medicine ,business ,Cells, Cultured ,media_common - Abstract
Serendipity has played a significant role throughout the history of drug discovery in general and, in particular, throughout the history of cardiovascular medicine. The anticoagulant properties of dicoumarol were discovered after farmers observed that their cattle were dying of internal hemorrhaging after feeding on rotting sweet clover,1 and digitoxin was identified when the condition of a patient suffering from congestive heart failure dramatically improved after being given an herbal remedy containing extracts of the foxglove plant.2 In fact, many of the most effective pharmacological agents in use today arose through serendipity. Despite the historical role of serendipity in drug discovery, it is clear that such events occur too rarely to be counted on as consistent sources of future drug discovery. Over the past 3 decades, the standard drug discovery paradigm has shifted more and more toward a target-based approach, in which specific proteins are chosen, on the basis of the current understanding of disease mechanisms, as “targets” for drug discovery efforts. Once a target has been identified, high-throughput screening can often identify small molecules that inhibit the target’s activity, and, in some cases, these molecules can be developed further as drugs. Well-validated targets can lead to successful drugs, but for many cardiovascular diseases, it remains difficult to predict which targets will offer a therapeutic benefit. Recently developed genomic and proteomic techniques, including gene expression profiling, RNA interference, and in silico molecular modeling, have generated long lists of potential drug targets, but determining which of the potential targets actually have therapeutic value has been much more difficult. Much of the difficulty involves predicting which targets will reverse disease processes, especially when dealing with diseases with complex underlying biology. Indeed, the high rates of cumulative attrition of supposedly validated drug candidates are consistent with a recent study by the Congressional … more...
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- 2009
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37. Small molecule screen for compounds that affect vascular development in the zebrafish retina
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Kyle J. McCulloch, Jarema Malicki, Satish Srinivas Kitambi, and Randall T. Peterson
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Embryology ,Angiogenesis ,Blood vessel morphogenesis ,Albendazole ,Article ,Small Molecule Libraries ,chemistry.chemical_compound ,medicine ,Animals ,Zebrafish ,Process (anatomy) ,Retina ,biology ,Retinal Vessels ,Retinal ,Anatomy ,biology.organism_classification ,Cell biology ,Mebendazole ,Phenotype ,medicine.anatomical_structure ,chemistry ,cardiovascular system ,sense organs ,Developmental biology ,Developmental Biology ,Blood vessel - Abstract
Blood vessel formation in the vertebrate eye is a precisely regulated process. In the human retina, both an excess and a deficiency of blood vessels may lead to a loss of vision. To gain insight into the molecular basis of vessel formation in the vertebrate retina and to develop pharmacological means of manipulating this process in a living organism, we further characterized the embryonic zebrafish eye vasculature, and performed a small molecule screen for compounds that affect blood vessel morphogenesis. The screening of approximately 2000 compounds revealed four small molecules that at specific concentrations affect retinal vessel morphology but do not produce obvious changes in trunk vessels, or in the neuronal architecture of the retina. Of these, two induce a pronounced widening of vessel diameter without a substantial loss of vessel number, one compound produces a loss of retinal blood vessels accompanied by a mild increase of their diameter, and finally one other generates a severe loss of retinal vessels. This work demonstrates the utility of zebrafish as a screening tool for small molecules that affect eye vasculature and presents several compounds of potential therapeutic importance. more...
- Published
- 2009
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38. BMP type I receptor inhibition reduces heterotopic ossification
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Tomokazu Fukuda, Mary L. Bouxsein, Yuji Mishina, Kenneth D. Bloch, Nobuhiro Kamiya, Gregory D. Cuny, Carol S. Lai, Charles C. Hong, Deborah W. Hong, Patrick M. McManus, Paul B. Yu, Chetana Sachidanandan, Donna Y. Deng, Takenobu Katagiri, and Randall T. Peterson more...
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medicine.medical_specialty ,ACVR1 ,Bone morphogenetic protein ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,Internal medicine ,medicine ,Animals ,Bone morphogenetic protein receptor ,Kinase activity ,Bone Morphogenetic Protein Receptors, Type I ,Molecular Structure ,Ossification ,business.industry ,Ossification, Heterotopic ,General Medicine ,medicine.disease ,BMPR2 ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Pyrimidines ,Endocrinology ,Myositis Ossificans ,Fibrodysplasia ossificans progressiva ,Pyrazoles ,Heterotopic ossification ,medicine.symptom ,Tomography, X-Ray Computed ,business ,Signal Transduction - Abstract
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues1–4 and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2)5. Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid treatment inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling. more...
- Published
- 2008
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39. Cisplatin Analogs Confer Protection against Cyanide Poisoning
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Matthew Brenner, Robert E. Gerszten, Xu Shi, Jangwoen Lee, Gerry R. Boss, Sari B. Mahon, Devin L. Harrison, Jordan Morningstar, Patrick Sips, Randall T. Peterson, Anjali K. Nath, Adriano Chan, and Calum A. MacRae more...
- Subjects
0301 basic medicine ,Cyanide ,Antidotes ,Clinical Biochemistry ,Pharmacology ,Biochemistry ,Article ,Cell Line ,Electron Transport Complex IV ,Lethal Dose 50 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Detoxification ,Drug Discovery ,medicine ,Animals ,Humans ,Drug Approval ,Molecular Biology ,Cyanide anion ,Zebrafish ,Cisplatin ,Cyanides ,Chemistry ,Small molecule ,030104 developmental biology ,Solubility ,030220 oncology & carcinogenesis ,Toxicity ,Molecular Medicine ,%22">Fish ,Cyanide poisoning ,Rabbits ,Oxidation-Reduction ,Sulfur ,medicine.drug - Abstract
Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cyanide kills organisms as diverse as insects, fish, and humans within seconds to hours. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro. We therefore screened a panel of diverse cisplatin analogs and identified compounds that conferred protection from cyanide poisoning in zebrafish, mice, and rabbits. Cumulatively, this discovery pipeline begins to establish the characteristics of platinum ligands that influence their solubility, toxicity, and efficacy, and provides proof of concept that platinum-based complexes are effective antidotes for cyanide poisoning. more...
- Published
- 2017
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40. Coalescence Extraction: A Novel, Rapid Means of Performing Solvent Extractions
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Randall T. Peterson and John D. Lamb
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Coalescence (physics) ,Aqueous solution ,Chromatography ,Chemistry ,Process Chemistry and Technology ,General Chemical Engineering ,Extraction (chemistry) ,Mixing (process engineering) ,Filtration and Separation ,General Chemistry ,Solvent ,chemistry.chemical_compound ,Glutaronitrile ,Solvent extraction - Abstract
We report the development of a novel solvent extraction technique which exploits the coalescence properties exhibited by some solvent combinations at elevated temperatures. The technique allows for instantaneous mixing which approaches the theoretical extraction limit. In the extraction of Pb2+ from aqueous solution into either 2,4-pentanedione or glutaronitrile containing dicyclohexano-18-crown-6 (DC18C6), extraction times were reduced from 2 hours to less than 1 minute. The K ex value for extracting Pb2+ into glutaronitrile with DC18C6 as the extractant was determined to be 260. The novel coalescence extraction technique is compared to traditional systems in terms of extraction efficiency, speed of extraction, and feasibility of practical applications. more...
- Published
- 1995
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41. Chemical biology and the limits of reductionism
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Randall T. Peterson
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Reductionism ,Systems biology ,Ecology (disciplines) ,Chemistry, Pharmaceutical ,Research ,Chemical biology ,Mindset ,Cell Biology ,Computational biology ,Marine Biology (journal) ,Biology ,Ecology and Evolutionary Biology ,Models, Biological ,Epistemology ,Drug Delivery Systems ,Knowledge ,Science policy ,Molecular Biology - Abstract
Chemical biology and systems biology have grown and evolved in parallel during the past decade, but the mindsets of the two disciplines remain quite different. As the inevitable intersections between the disciplines become more frequent, chemical biology has an opportunity to assimilate the most powerful ideas from systems biology. Can the integrationist mindset of systems biology liberate chemical biology from the compulsion to reduce everything to individual small molecule–target pairings? more...
- Published
- 2008
42. Chemobehavioural phenomics and behaviour-based psychiatric drug discovery in the zebrafish
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David Kokel and Randall T. Peterson
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medicine.medical_specialty ,biology ,Behavior, Animal ,Extramural ,Drug discovery ,biology.organism_classification ,Biochemistry ,Phenomics ,Drug Discovery ,Papers ,Genetics ,medicine ,Animals ,Psychiatric drugs ,Psychiatry ,Molecular Biology ,Zebrafish ,Chemical genetics ,Antipsychotic Agents - Abstract
Despite their ubiquity and impact, psychiatric illnesses and other disorders of the central nervous system remain among the most poorly treated diseases. Most psychiatric medicines were discovered due to serendipitous observations of behavioural phenotypes in humans, rodents and other mammals. Extensive behaviour-based chemical screens would likely identify novel psychiatric drugs. However, large-scale chemical screens in mammals are inefficient and impractical. In contrast, zebrafish are very well suited for high-throughput behaviour-based drug discovery. Furthermore, the vast amounts of data generated from large-scale behavioural screens in zebrafish will facilitate a systems-level analysis of how chemicals affect behaviour. Unlike serendipitous discoveries in mammals, a comprehensive and integrative analysis of zebrafish chemobehavioural phenomics may identify functional relationships that would be missed by more reductionist approaches. Thus, behaviour-based chemical screens in the zebrafish may improve our understanding of neurobiology and accelerate the pace of psychiatric drug discovery. more...
- Published
- 2008
43. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells
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Jijun Hao, Jianyong Hu, Antonis K. Hatzopoulos, Clare K. Murphy, Joshua N. Ho, Paul B. Yu, Charles C. Hong, Randall T. Peterson, and Marie A. Daleo
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Male ,Cell signaling ,Urban Population ,Cellular differentiation ,medicine.medical_treatment ,Cell Biology/Developmental Molecular Mechanisms ,lcsh:Medicine ,Biology ,Bone morphogenetic protein ,Cell Biology/Cell Signaling ,Hemoglobins ,03 medical and health sciences ,0302 clinical medicine ,Chemical Biology ,medicine ,Humans ,Blood Transfusion ,Myocytes, Cardiac ,Induced pluripotent stem cell ,lcsh:Science ,Embryonic Stem Cells ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Multidisciplinary ,Anemia, Iron-Deficiency ,lcsh:R ,Infant ,Cell Differentiation ,Stem-cell therapy ,Embryonic stem cell ,Developmental Biology/Stem Cells ,3. Good health ,Cell biology ,Endothelial stem cell ,Pyrimidines ,Child, Preschool ,030220 oncology & carcinogenesis ,Bone Morphogenetic Proteins ,Immunology ,Developmental Biology/Cell Differentiation ,Pyrazoles ,Female ,lcsh:Q ,Stem cell ,Child, Hospitalized ,Signal Transduction ,Research Article - Abstract
Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/ Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. QuantitativePCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/ Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine. more...
- Published
- 2008
44. A noncanonical path to mechanism of action
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Randall T. Peterson
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Stereochemistry ,Clinical Biochemistry ,Embryonic Development ,Angiogenesis Inhibitors ,Computational biology ,Biochemistry ,Aminopeptidases ,Wnt-5a Protein ,Article ,Mice ,Cyclohexanes ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,RNA, Antisense ,Fumagillin ,Zebrafish ,Molecular Biology ,Pharmacology ,O-(Chloroacetylcarbamoyl)fumagillol ,biology ,Mechanism (biology) ,Chemistry ,Wnt signaling pathway ,Metalloendopeptidases ,General Medicine ,Zebrafish Proteins ,biology.organism_classification ,Angiogenesis inhibitor ,Wnt Proteins ,Phenotype ,Mechanism of action ,Fatty Acids, Unsaturated ,Molecular Medicine ,medicine.symptom ,Sesquiterpenes ,medicine.drug ,Signal Transduction - Abstract
Previous mode of action studies identified methionine aminopeptidase 2 (MetAP-2) as the target of the anti-angiogenic natural product fumagillin and its drug candidate analog, TNP-470. We report here that TNP-470-mediated MetAP-2 inhibition blocks noncanonical Wnt signaling, which plays a critical role in development, cell differentiation, and tumorigenesis. Consistent with this finding, antisense MetAP-2 morpholino oligonucleotide injection in zebrafish embryos pheno-copies gastrulation defects seen in noncanonical Wnt5 loss-of-function zebrafish mutants. MetAP-2 inhibition or depletion blocks signaling downstream of the Wnt receptor Frizzled, but upstream of Calmodulin-dependent Kinase II, RhoA, and c-Jun N-terminal Kinase. Moreover, we demonstrate that TNP-470 does not block the canonical Wnt/β-catenin pathway. Thus, TNP-470 selectively regulates noncanonical over canonical Wnt signaling and provides a unique means to explore and dissect the biological systems mediated by these pathways. more...
- Published
- 2006
45. In vivo drug discovery in the zebrafish
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Leonard I. Zon and Randall T. Peterson
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Pharmacology ,ved/biology ,Drug discovery ,fungi ,ved/biology.organism_classification_rank.species ,Drug Evaluation, Preclinical ,General Medicine ,Computational biology ,Biology ,Bioinformatics ,biology.organism_classification ,Phenotype ,Disease modelling ,Drug development ,In vivo ,Drug Design ,Drug Discovery ,Models, Animal ,Toxicity Tests ,Animals ,Humans ,Identification (biology) ,Model organism ,Zebrafish - Abstract
The zebrafish has become a widely used model organism because of its fecundity, its morphological and physiological similarity to mammals, the existence of many genomic tools and the ease with which large, phenotype-based screens can be performed. Because of these attributes, the zebrafish might also provide opportunities to accelerate the process of drug discovery. By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish promises to contribute to several aspects of the drug development process, including target identification, disease modelling, lead discovery and toxicology. more...
- Published
- 2005
46. Propping up a destructive regime
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Randall T. Peterson
- Subjects
Cell signaling ,Multidisciplinary ,Structural biology ,Drug discovery ,Systems biology ,Computational biology ,Signal transduction ,Biology ,Proteomics ,Anticancer drug ,Functional genomics ,Cell biology - Abstract
The Wnt signalling pathway balances the opposing activities of two proteins to transmit signals within cells. An inhibitor that stabilizes one of these proteins reveals a new target for anticancer drug development. more...
- Published
- 2009
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47. Novel Wnt antagonists target porcupine and Axin
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Randall T. Peterson and Jing-Ruey J. Yeh
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Cell signaling ,Structural biology ,Drug discovery ,Systems biology ,Wnt signaling pathway ,Cell Biology ,Computational biology ,Biology ,Signal transduction ,Bristle ,Molecular Biology ,Developmental biology ,Cell biology - Abstract
Wnt signals are seemingly ubiquitous in biology, controlling processes as diverse as bristle patterning in flies and tissue regeneration in humans. A new report describes the discovery of small molecules that inhibit Wnt signaling by two unprecedented mechanisms, paving the way for fundamental studies and perhaps improved treatment of colon cancer. more...
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- 2009
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48. Zebrafish-Based Small Molecule Discovery
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Calum A. MacRae and Randall T. Peterson
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Central Nervous System ,Embryo, Nonmammalian ,Cloning, Organism ,Phenotypic screening ,Clinical Biochemistry ,ved/biology.organism_classification_rank.species ,Drug Evaluation, Preclinical ,Context (language use) ,Computational biology ,Bioinformatics ,Cardiovascular System ,Biochemistry ,Drug Discovery ,Animals ,Genetic Testing ,Model organism ,Molecular Biology ,Zebrafish ,Organism ,Skin ,Pharmacology ,Organisms, Genetically Modified ,biology ,ved/biology ,Ear ,General Medicine ,biology.organism_classification ,Small molecule ,In vitro ,Disease Models, Animal ,Phenotype ,Models, Animal ,Molecular Medicine ,Developmental biology - Abstract
The earliest examples of small molecule discovery involved serendipitous phenotypic observations in whole organisms, but this organism-based process has given way in recent decades to systematic, high-throughput assays using purified proteins, cells, or cell extracts. In vitro screens have been successful at identifying modifiers of well-understood biological processes, but they are limited in their ability to discover modifiers of processes that are poorly understood or occur only in an integrated physiological context. Small model organisms, especially the zebrafish, make it possible to combine the advantages of organism-based small molecule discovery with the technologies and throughput of modern screening. The combination of model organisms with high-throughput screening is likely to extend small molecule discovery efforts to fields of study such as developmental biology and to broaden the range of diseases for which drug screening can be performed. more...
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49. New Mechanisms of 5-Nitrofuran Toxicity
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Randall T. Peterson
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Pharmacology ,medicine.drug_class ,Clinical Biochemistry ,General Medicine ,Computational biology ,Biology ,Biochemistry ,Drug Discovery ,medicine ,Molecular Medicine ,Identification (biology) ,Nifurtimox ,Nitrofuran ,Molecular Biology ,Fish skin ,medicine.drug - Abstract
Phenotypic screens and the target identification that follows can lead to surprising new connections between small molecules and targets. In this issue of Chemistry & Biology, Zhou and colleagues seek to understand the pigmentation of fish skin and end up uncovering an interesting clinical hypothesis about the trypanocidal compound nifurtimox. more...
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50. Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis
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Hagit Goldshtein, Alexandre Muhire, Virginie Petel Légaré, Avital Pushett, Ron Rotkopf, Jeremy M. Shefner, Randall T Peterson, Gary A. B. Armstrong, and Niva Russek‐ Blum
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective To evaluate the efficacy of a fixed‐dose combination of two approved drugs, Ciprofloxacin and Celecoxib, as a potential therapeutic treatment for amyotrophic lateral sclerosis (ALS). Methods Toxicity and efficacy of Ciprofloxacin and Celecoxib were tested, each alone and in distinct ratio combinations in SOD1 G93R transgenic zebrafish model for ALS. Quantification of swimming measures following stimuli, measurements of axonal projections from the spinal cord, neuromuscular junction structure and morphometric analysis of microglia cells were performed in the combination‐ treated vs nontreated mutant larvae. Additionally, quantifications of touch‐evoked locomotor escape response were conducted in treated vs nontreated zebrafish expressing the TARDBP G348C ALS variant. Results When administered individually, Ciprofloxacin had a mild effect and Celecoxib had no therapeutic effect. However, combined Ciprofloxacin and Celecoxib (Cipro/Celecox) treatment caused a significant increase of ~ 84% in the distance the SOD1 G93R transgenic larvae swam. Additionally, Cipro/Celecox elicited recovery of impaired motor neurons morphology and abnormal neuromuscular junction structure and preserved the ramified morphology of microglia cells in the SOD1 mutants. Furthermore, larvae expressing the TDP‐43 mutation displayed evoked touch responses that were significantly longer in swim distance (110% increase) and significantly higher in maximal swim velocity (~44% increase) when treated with Cipro/Celecox combination. Interpretation Cipro/Celecox combination improved locomotor and cellular deficits of ALS zebrafish models. These results identify this novel combination as effective, and may prove promising for the treatment of ALS. more...
- Published
- 2020
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