10 results on '"Pedrioli, Deena M. Leslie"'
Search Results
2. Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy.
- Author
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Allen, Edwin H. A., Courtney, David G., Atkinson, Sarah D., Moore, Johnny E., Mairs, Laura, Poulsen, Ebbe Toftgaard, Schiroli, Davide, Maurizi, Eleonora, Cole, Christian, Hickerson, Robyn P., James, John, Murgatroyd, Helen, Smith, Frances J. D., MacEwen, Carrie, Enghild, Jan J., Nesbit, M. Andrew, Pedrioli, Deena M. Leslie, McLean, W. H. Irwin, and Moore, C. B. Tara
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- 2016
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3. Identification of PARP-Specific ADP-Ribosylation Targets Reveals a Regulatory Function for ADP-Ribosylation in Transcription Elongation.
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Leutert, Mario, Pedrioli, Deena M. Leslie, and Hottiger, Michael O.
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POLY ADP ribose , *ADP-ribosylation , *GENETIC transcription regulation , *ELONGATION factors (Biochemistry) , *RNA polymerase II , *PROMOTERS (Genetics) - Abstract
In a recent issue of Science , Gibson et al. (2016) describe an in vitro chemical genetic approach that maps the specific ADP-ribosylation sites targeted by the ADP-ribosyltransferases PARP-1, PARP-2, and PARP-3 and demonstrate that PARP-1 regulates RNA polymerase II promoter-proximal pausing. [ABSTRACT FROM AUTHOR]
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- 2016
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4. Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death.
- Author
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Lin Liu, Sandow, Jarrod J., Pedrioli, Deena M. Leslie, Samson, Andre L., Silke, Natasha, Kratina, Tobias, Ambrose, Rebecca L., Doerflinger, Marcel, Zhaoqing Hu, Morrish, Emma, Diep Chau, Kueh, Andrew J., Fitzibbon, Cheree, Pellegrini, Marc, Pearson, Jaclyn S., Hottiger, Michael O., Webb, Andrew I., Lalaoui, Najoua, and Silke, John
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CELL death , *DEATH receptors , *DOXYCYCLINE , *LIFE sciences , *ADP-ribosylation , *SARS-CoV-2 , *GREEN fluorescent protein - Abstract
The article presents a study which explores that Tankyrase-mediated ADP-ribosylation, a regulator of Tumor necrosis factor (TNF)-induced death . It mentions that findings of the study suggests that disruption of ADP-ribosylation during an infection can prime a cell to retaliate with an inflammatory cell death.
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- 2022
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5. miR-31 Functions as a Negative Regulator of Lymphatic Vascular Lineage-Specific Differentiation In Vitro and Vascular Development In Vivo.
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Pedrioli, Deena M. Leslie, Karpanen, Terhi, Dabouras, Vasilios, Jurisic, Giorgia, van de Hoek, Glenn, Shin, Jay W., Marino, Daniela, Kälin, Roland E., Leidel, Sebastian, Cinelli, Paolo, Schulte-Merker, Stefan, Brändli, André W., and Detmar, Michael
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LYMPHATICS , *HOMEOSTASIS , *IMMUNE response , *METASTASIS , *CANCER genetics - Abstract
The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses, and promotes cancer metastasis. To address the role microRNAs (miRNAs) play in the development and function of the lymphatic vascular system, we defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) and identified four BVEC signature and two LEC signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR and in situ hybridization. Functional characterization of the BVEC signature miRNA miR-31 identified a novel BVEC-specific posttranscriptional regulatory mechanism that inhibits the expression of lymphatic lineage-specific transcripts in vitro. We demonstrate that suppression of lymphatic differentiation is partially mediated via direct repression of PROX1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation. Finally, in vivo studies of Xenopus and zebrafish demonstrated that gain of miR-31 function impaired venous sprouting and lymphatic vascular development, thus highlighting the importance of miR-31 as a negative regulator of lymphatic development. Collectively, our findings identify miR-31 is a potent regulator of vascular lineage-specific differentiation and development in vertebrates. [ABSTRACT FROM AUTHOR]
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- 2010
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6. Keratin 9 Is Required for the Structural Integrity and Terminal Differentiation of the Palmoplantar Epidermis.
- Author
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Fu, Dun Jack, Thomson, Calum, Lunny, Declan P, Dopping-Hepenstal, Patricia J, McGrath, John A, Smith, Frances J D, Irwin McLean, W H, and Pedrioli, Deena M Leslie
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CELL differentiation , *KERATIN , *EPIDERMIS , *GENE expression , *GENETIC mutation , *EPIDERMOLYSIS bullosa , *PHYSIOLOGY - Abstract
Keratin 9 (K9) is a type I intermediate filament protein whose expression is confined to the suprabasal layers of the palmoplantar epidermis. Although mutations in the K9 gene are known to cause epidermolytic palmoplantar keratoderma, a rare dominant-negative skin disorder, its functional significance is poorly understood. To gain insight into the physical requirement and importance of K9, we generated K9-deficient (Krt9−/−) mice. Here, we report that adult Krt9−/−mice develop calluses marked by hyperpigmentation that are exclusively localized to the stress-bearing footpads. Histological, immunohistochemical, and immunoblot analyses of these regions revealed hyperproliferation, impaired terminal differentiation, and abnormal expression of keratins K5, K14, and K2. Furthermore, the absence of K9 induces the stress-activated keratins K6 and K16. Importantly, mice heterozygous for the K9-null allele (Krt9+/−) show neither an overt nor histological phenotype, demonstrating that one Krt9 allele is sufficient for the developing normal palmoplantar epidermis. Together, our data demonstrate that complete ablation of K9 is not tolerable in vivo and that K9 is required for terminal differentiation and maintaining the mechanical integrity of palmoplantar epidermis. [ABSTRACT FROM AUTHOR]
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- 2014
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7. Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation.
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Hopp, Ann-Katrin, Teloni, Federico, Bisceglie, Lavinia, Gondrand, Corentin, Raith, Fabio, Nowak, Kathrin, Muskalla, Lukas, Howald, Anna, Pedrioli, Patrick G.A., Johnsson, Kai, Altmeyer, Matthias, Pedrioli, Deena M. Leslie, and Hottiger, Michael O.
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NAD (Coenzyme) , *MITOCHONDRIA , *MASS spectrometry , *HYDROGEN peroxide , *OXIDATIVE stress , *NICOTINAMIDE - Abstract
In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD+) is an important co-factor for enzymatic reactions, including ADP-ribosylation. Although mitochondria harbor the most intra-cellular NAD+, mitochondrial ADP-ribosylation remains poorly understood. Here we provide evidence for mitochondrial ADP-ribosylation, which was identified using various methodologies including immunofluorescence, western blot, and mass spectrometry. We show that mitochondrial ADP-ribosylation reversibly increases in response to respiratory chain inhibition. Conversely, H 2 O 2 -induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation. Elevated mitochondrial ADP-ribosylation, in turn, dampens H 2 O 2 -triggered nuclear ADP-ribosylation and increases MMS-induced ARTD1 chromatin retention. Interestingly, co-treatment of cells with the mitochondrial uncoupler FCCP decreases PARP inhibitor efficacy. Together, our results suggest that mitochondrial ADP-ribosylation is a dynamic cellular process that impacts nuclear ADP-ribosylation and provide evidence for a NAD+-mediated mitochondrial-nuclear crosstalk. • Mitochondrial ADP-ribosylation was identified by different methods • Mitochondrial ADP-ribosylation reversibly increased after respiratory chain inhibition • H 2 O 2 treatment induces nuclear and reduces mitochondrial ADP-ribosylation • Elevated mitochondrial ADP-ribosylation dampened MMS-induced ARTD1 chromatin retention Hopp et al. detect mitochondrial ADP-ribosylation and characterize its dependency on intracellular NAD+ homeostasis. While respiratory chain inhibition increases mitochondrial ADP-ribosylation, hydrogen peroxide treatment reduces mitochondrial ADP-ribosylation and reciprocally induces nuclear ADP-ribosylation. This dynamic and reversable process is dependent on a NAD+-dependent mitochondrial-nuclear crosstalk. [ABSTRACT FROM AUTHOR]
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- 2021
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8. In vivo gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation.
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Hegde V, Hickerson RP, Nainamalai S, Campbell PA, Smith FJ, McLean WH, and Pedrioli DM
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- Administration, Topical, Animals, Chemistry, Pharmaceutical, Drug Delivery Systems, Epidermis drug effects, Filaggrin Proteins, Genes, Reporter drug effects, Humans, Injections, Intradermal, Intermediate Filament Proteins administration & dosage, Intermediate Filament Proteins genetics, Mice, RNA, Small Interfering administration & dosage, Gene Silencing, Genetic Therapy methods, RNA, Small Interfering therapeutic use
- Abstract
Therapeutics based on short interfering RNAs (siRNAs), which act by inhibiting the expression of target transcripts, represent a novel class of potent and highly specific next-generation treatments for human skin diseases. Unfortunately, the intrinsic barrier properties of the skin combined with the large size and negative charge of siRNAs make epidermal delivery of these macromolecules quite challenging. To help evaluate the in vivo activity of these therapeutics and refine delivery strategies we generated an innovative reporter mouse model that predominantly expresses firefly luciferase (luc2p) in the paw epidermis--the region of murine epidermis that most closely models the tissue architecture of human skin. Combining this animal model with state-of-the-art live animal imaging techniques, we have developed a real-time in vivo analysis work-flow that has allowed us to compare and contrast the efficacies of a wide range nucleic acid-based gene silencing reagents in the skin of live animals. While inhibition was achieved with all of the reagents tested, only the commercially available "self-delivery" modified Accell-siRNAs (Dharmacon) produced potent and sustained in vivo gene silencing. Together, these findings highlight just how informative reliable reporter mouse models can be when assessing novel therapeutics in vivo. Using this work-flow, we developed a novel clinically-relevant topical formulation that facilitates non-invasive epidermal delivery of unmodified and "self-delivery" siRNAs. Remarkably, a sustained >40% luc2p inhibition was observed after two 1-hour treatments with Accell-siRNAs in our topical formulation. Importantly, our ability to successfully deliver siRNA molecules topically brings these novel RNAi-based therapeutics one-step closer to clinical use., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)
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- 2014
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9. siRNA silencing of the mutant keratin 12 allele in corneal limbal epithelial cells grown from patients with Meesmann's epithelial corneal dystrophy.
- Author
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Courtney DG, Atkinson SD, Allen EH, Moore JE, Walsh CP, Pedrioli DM, MacEwen CJ, Pellegrini G, Maurizi E, Serafini C, Fantacci M, Liao H, Irvine AD, McLean WH, and Moore CB
- Subjects
- Alleles, Cell Proliferation, Cells, Cultured, Corneal Dystrophy, Juvenile Epithelial of Meesmann metabolism, Corneal Dystrophy, Juvenile Epithelial of Meesmann pathology, Enzyme-Linked Immunosorbent Assay, Exons, Heterozygote, Humans, Immunohistochemistry, Keratin-12 metabolism, Limbus Corneae metabolism, Pedigree, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Corneal Dystrophy, Juvenile Epithelial of Meesmann genetics, DNA genetics, Keratin-12 genetics, Limbus Corneae pathology, Mutation, Missense
- Abstract
Purpose: The aim of this study is to further assess our previously reported keratin 12 (K12)-Leu132Pro specific siRNA in silencing the mutant allele in Meesmann's Epithelial Corneal Dystrophy (MECD) in experimental systems more akin to the in vivo situation through simultaneous expression of both wild-type and mutant alleles., Methods: Using KRT12 exogenous expression constructs transfected into cells, mutant allele specific knockdown was quantified using pyrosequencing and infrared Western blot analysis, while the silencing mechanism was assessed by a modified rapid amplification of cDNA ends (5'RACE) method. Corneal limbal biopsies taken from patients suffering from MECD were used to establish cultures of MECD corneal limbal epithelial stem cells and the ability of the siRNA to silence the endogenous mutant KRT12 allele was assessed by a combination of pyrosequencing, qPCR, ELISA, and quantitative-fluorescent immunohistochemistry (Q-FIHC)., Results: The siRNA displayed a potent and specific knockdown of K12-Leu132Pro at both the mRNA and protein levels with exogenous expression constructs. Analysis by the 5'RACE method confirmed siRNA-mediated cleavage. In the MECD cells, an allele-specific knockdown of 63% of the endogenous mutant allele was observed without effect on wild-type allele expression., Conclusions: Combined with an effective delivery vehicle this siRNA approach represents a viable treatment option for prevention of the MECD pathology observed in K12-Leu132Pro heterozygous individuals., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)
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- 2014
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10. Allele-specific siRNA silencing for the common keratin 12 founder mutation in Meesmann epithelial corneal dystrophy.
- Author
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Allen EHA, Atkinson SD, Liao H, Moore JE, Pedrioli DML, Smith FJD, McLean WHI, and Moore CBT
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- Alleles, Cell Culture Techniques, Corneal Dystrophy, Juvenile Epithelial of Meesmann metabolism, Corneal Dystrophy, Juvenile Epithelial of Meesmann pathology, Exons, Humans, Keratin-12 metabolism, Mutant Proteins genetics, Mutant Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Corneal Dystrophy, Juvenile Epithelial of Meesmann genetics, DNA genetics, Gene Silencing, Keratin-12 genetics, Mutation, RNA, Small Interfering genetics
- Abstract
Purpose: To identify an allele-specific short interfering RNA (siRNA), against the common KRT12 mutation Arg135Thr in Meesmann epithelial corneal dystrophy (MECD) as a personalized approach to treatment., Methods: siRNAs against the K12 Arg135Thr mutation were evaluated using a dual luciferase reporter gene assay and the most potent and specific siRNAs were further screened by Western blot. Off-target effects on related keratins were assessed and immunological stimulation of TLR3 was evaluated by RT-PCR. A modified 5' rapid amplification of cDNA ends method was used to confirm siRNA-mediated mutant knockdown. Allele discrimination was confirmed by quantitative infrared immunoblotting., Results: The lead siRNA, with an IC(50) of thirty picomolar, showed no keratin off-target effects or activation of TLR3 in the concentration ranges tested. We confirmed siRNA-mediated knockdown by the presence of K12 mRNA fragments cleaved at the predicted site. A dual tag infrared immunoblot showed knockdown to be allele-specific, with 70% to 80% silencing of the mutant protein., Conclusions: A potent allele-specific siRNA against the K12 Arg135Thr mutation was identified. In combination with efficient eyedrop formulation delivery, this would represent a personalized medicine approach, aimed at preventing the pathology associated with MECD and other ocular surface pathologies with dominant-negative or gain-of-function pathomechanisms.
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- 2013
- Full Text
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