Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing
| Autor: | Tatiana Kisseleva, Isin Dalkilic-Liddle, David A. Brenner, Tatiana Novobrantseva, Taylor L. Reynolds, Jeremy S. Duffield, Daniel G. Anderson, Victor Koteliansky, Aldo Amatucci, Elisabeth H. Vollmann, Faryal F. Mir, Stefan Hamann, Lizhi Cao, Thomas Cameron, Markus Hossbach, Linda C. Burkly, Kevin J. Kauffman |
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| Přispěvatelé: | Massachusetts Institute of Technology. Dept. of Chemical Engineering., Harvard University--MIT Division of Health Sciences and Technology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Small interfering RNA LNP Clinical Sciences Biology 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Fibrosis Drug Discovery Gene expression medicine Gene silencing Progenitor cell lcsh:RM1-950 fibrosis medicine.disease myofibroblast RNA silencing lcsh:Therapeutics. Pharmacology 030104 developmental biology 030220 oncology & carcinogenesis siRNA Cancer research in vivo gene silencing Molecular Medicine Original Article Egr2 Biochemistry and Cell Biology Myofibroblast |
| Zdroj: | Elsevier Molecular Therapy: Nucleic Acids, Vol 7, Iss C, Pp 314-323 (2017) Molecular Therapy. Nucleic Acids |
| Popis: | Fibrotic diseases contribute to 45% of deaths in the industrialized world, and therefore a better understanding of the pathophysiological mechanisms underlying tissue fibrosis is sorely needed. We aimed to identify novel modifiers of tissue fibrosis expressed by myofibroblasts and their progenitors in their disease microenvironment through RNA silencing in vivo. We leveraged novel biology, targeting genes upregulated during liver and kidney fibrosis in this cell lineage, and employed small interfering RNA (siRNA)-formulated lipid nanoparticles technology to silence these genes in carbon-tetrachloride-induced liver fibrosis in mice. We identified five genes, Egr2, Atp1a2, Fkbp10, Fstl1, and Has2, which modified fibrogenesis based on their silencing, resulting in reduced Col1a1 mRNA levels and collagen accumulation in the liver. These genes fell into different groups based on the effects of their silencing on a transcriptional mini-array and histological outcomes. Silencing of Egr2 had the broadest effects in vivo and also reduced fibrogenic gene expression in a human fibroblast cell line. Prior to our study, Egr2, Atp1a2, and Fkbp10 had not been functionally validated in fibrosis in vivo. Thus, our results provide a major advance over the existing knowledge of fibrogenic pathways. Our study is the first example of a targeted siRNA assay to identify novel fibrosis modifiers in vivo. Graphical Abstract |
| Databáze: | OpenAIRE |
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