4 results on '"Bogorad, Roman L"'
Search Results
2. Control of liver size by RNAi-mediated multiplex knockdown and its application for discovery of regulatory mechanisms
- Author
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Yin, Hao, Bogorad, Roman L., Barnes, Carmen, Walsha, Stephen, Zhuang, Iris, Nonaka, Hidenori, Ruda, Vera, Kuchimanchi, Satya, Nechev, Lubomir, Akinc, Akin, Xue, Wen, Zerial, Marino, Langer, Robert, Anderson, Daniel G., and Koteliansky, Victor
- Subjects
Hepatocyte Growth Factor ,Gene Expression ,Cell Cycle Proteins ,YAP-Signaling Proteins ,Genomics ,Organ Size ,Protein Serine-Threonine Kinases ,Phosphoproteins ,Serine-Threonine Kinase 3 ,Article ,Mice, Inbred C57BL ,Mice ,Liver ,Genes, Neurofibromatosis 2 ,Proto-Oncogene Proteins ,Animals ,Nanoparticles ,RNA Interference ,Tumor Suppressor Protein p53 ,Adaptor Proteins, Signal Transducing ,Hepatomegaly - Abstract
The Hippo pathway controls organ size through a negative regulation of the transcription co-activator Yap1. The overexpression of hyperactive mutant Yap1 or deletion of key components in the Hippo pathway leads to increased organ size in different species. Analysis of interactions of this pathway with other cellular signals corroborating organ size control is limited in part due to the difficulties associated with development of rodent models.Here, we develop a new model of reversible induction of the liver size in mice using siRNA-nanoparticles targeting two kinases of the Hippo pathway, namely, mammalian Ste20 family kinases 1 and 2 (Mst1 and Mst2), and an upstream regulator, neurofibromatosis type II (Nf2).The triple siRNAs nanoparticle-induced hepatomegaly in mice phenocopies one observed with Mst1(-/-)Mst2(-/-) liver-specific depletion, as shown by extensive proliferation of hepatocytes and activation of Yap1. The simultaneous co-treatment with a fourth siRNA nanoparticle against Yap1 fully blocked the liver growth. Hippo pathway-induced liver enlargement is associated with p53 activation, evidenced by its accumulation in the nuclei and upregulation of its target genes. Moreover, injections of the triple siRNAs nanoparticle in p53(LSL/LSL) mice shows that livers lacking p53 expression grow faster and exceed the size of livers in p53 wild-type animals, indicating a role of p53 in controlling Yap1-induced liver growth.Our data show that siRNA-nanoparticulate manipulation of gene expression can provide the reversible control of organ size in adult animals, which presents a new avenue for the investigation of complex regulatory networks in liver.
- Published
- 2015
3. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight
- Author
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Dganit Danino, Omar F. Khan, Klaus Charisse, Matthew J. Webber, Akin Akinc, Yizhou Dong, Tatiana Novobrantseva, Shan Jiang, Roman L. Bogorad, Vera M. Ruda, Matthias Nahrendorf, Taylor E. Shaw, Dayna K. Mudge, Rubin M. Tuder, Aude Thiriot, Andrew Bader, Daniel G. Anderson, Mark W. Kieran, Hendrik B. Sager, Tim Racie, Christopher G. Levins, Lauren Speciner, Partha Dutta, Ulrich H. von Andrian, Robert Langer, Mario F. Perez, Siddharth Jhunjunwala, Kevin Fitzgerald, Avi Schroeder, Kamaljeet Singh Sandhu, Dipak Panigrahy, James E. Dahlman, Ludmila Abezgauz, Lynelle P. Smith, Hao Yin, Danielle Seedorf, Abigail K. R. Lytton-Jean, Victor Koteliansky, Gaurav Sahay, Carmen M. Barnés, Brian T. Kalish, Yiping Xing, Apeksha Dave, Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Koch Institute for Integrative Cancer Research at MIT, Dahlman, James E., Khan, Omar F., Jhunjhunwala, Siddharth, Shaw, Taylor E., Xing, Yiping, Sahay, Gaurav, Bader, Andrew, Bogorad, Roman L., Yin, Hao, Dong, Yizhou, Jiang, Shan, Seedorf, Danielle, Dave, Apeksha, Sandhu, Kamaljeet Singh, Webber, Matthew, Ruda, Vera M., Lytton-Jean, Abigail K. R., Levins, Christopher G., Langer, Robert, and Anderson, Daniel Griffith
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Small interfering RNA ,Endothelium ,Polymers ,Biomedical Engineering ,Bioengineering ,Vascular permeability ,Nanotechnology ,Article ,Cell Line ,Mice ,In vivo ,RNA interference ,Neoplasms ,medicine ,Animals ,Humans ,Gene silencing ,General Materials Science ,RNA, Small Interfering ,Electrical and Electronic Engineering ,Chemistry ,Endothelial Cells ,Condensed Matter Physics ,Atomic and Molecular Physics, and Optics ,Cell biology ,medicine.anatomical_structure ,Cell culture ,Drug delivery ,Nanoparticles ,RNA Interference - Abstract
Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis., American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship, National Science Foundation (U.S.), Massachusetts Institute of Technology. Presidential Fellowship
- Published
- 2014
4. Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice
- Author
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Daniel G. Anderson, Roman L. Bogorad, Victor Koteliansky, Vera M. Ruda, Hidenori Nonaka, Anja Zeigerer, Marino Zerial, Hao Yin, Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Bogorad, Roman L., Yin, Hao, Ruda, Vera M., Anderson, Daniel Griffith, and Koteliansky, Victor
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Carcinoma, Hepatocellular ,Integrin beta Chains ,Cellular differentiation ,Cell ,Integrin ,General Physics and Astronomy ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Article ,Liver Neoplasms, Experimental ,Downregulation and upregulation ,medicine ,Gene Knockdown Techniques ,Animals ,RNA, Small Interfering ,Cell Proliferation ,Gene knockdown ,Multidisciplinary ,Integrin alpha Chains ,biology ,Chemistry ,Cell growth ,Integrin beta1 ,General Chemistry ,Proto-Oncogene Proteins c-met ,3. Good health ,Liver Regeneration ,medicine.anatomical_structure ,Liver ,Cancer research ,biology.protein ,Hepatocytes ,Nanoparticles - Abstract
Integrins play an important role during development, regulating cell differentiation, proliferation and survival. Here we show that knockdown of integrin subunits slows down the progression of hepatocellular carcinoma (HCC). Using nanoparticulate delivery of short interfering RNAs targeting β1 and αv integrin subunits, we downregulate all integrin receptors in hepatocytes. Short-term integrin knockdown (2 weeks) does not cause apparent structural or functional perturbations of normal liver tissue. Alterations in liver morphology accumulate on sustained integrin downregulation (7 weeks). The integrin knockdown leads to significant retardation of HCC progression, reducing proliferation and increasing tumour cell death. This tumour retardation is accompanied by reduced activation of the MET oncogene as well as expression of its mature form on the cell surface. Our data suggest that transformed proliferating cells from HCC are more sensitive to knockdown of integrins than normal quiescent hepatocytes, highlighting the potential of small interfering RNA-mediated inhibition of integrins as an anti-cancer therapeutic approach., Alnylam Pharmaceuticals (Firm), National Institutes of Health (U.S.) (RO1-DE016516), National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30CCA14051)
- Published
- 2013
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