Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing
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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2019
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| Online Access: | https://hdl.handle.net/1721.1/121997 |
| _version_ | 1811080680421982208 |
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| author | Kauffman, Kevin John Mir, Faryal Anderson, Daniel Griffith |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Kauffman, Kevin John Mir, Faryal Anderson, Daniel Griffith |
| author_sort | Kauffman, Kevin John |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:35:04Z |
| format | Article |
| id | mit-1721.1/121997 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:35:04Z |
| publishDate | 2019 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1219972022-10-01T04:36:28Z Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing Kauffman, Kevin John Mir, Faryal Anderson, Daniel Griffith Massachusetts Institute of Technology. Department of Chemical Engineering Harvard University--MIT Division of Health Sciences and Technology 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. 2019-08-19T12:10:43Z 2019-08-19T12:10:43Z 2017-06 2016-11 2019-08-09T13:24:37Z Article http://purl.org/eprint/type/JournalArticle 2162-2531 https://hdl.handle.net/1721.1/121997 Vollmann, Elizabeth H., Lizhi Cao, Aldo Amatucci, Taylor Reynolds, Stefan Hamann, Isin Dalkilic-Liddle, Thomas O. Cameron, Markus Hossbach, Kevin J. Kauffman, Faryal F. Mir, Daniel G. Anderson, Tatiana Novobrantseva, Victor Koteliansky, Tatiana Kisseleva, David Brenner, Jeremy Duffield, and Linda C. Burkly. "Identification of Novel Fibrosis Modifiersby In Vivo siRNA Silencing." Molecular Therapy: Nucleic Acids 7, June 2017 © 2017 The Author(s) en 10.1016/J.OMTN.2017.04.014 Molecular Therapy: Nucleic Acid Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Kauffman, Kevin John Mir, Faryal Anderson, Daniel Griffith Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing |
| title | Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing |
| title_full | Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing |
| title_fullStr | Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing |
| title_full_unstemmed | Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing |
| title_short | Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing |
| title_sort | identification of novel fibrosis modifiers by in vivo sirna silencing |
| url | https://hdl.handle.net/1721.1/121997 |
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