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Long noncoding RNAs regulating liver fibrosis

长链非编码RNA调节肝纤维化

基本信息

批准号：
10165705
负责人：
ALAN C MULLEN
金额：
$ 37.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165705
关键词：
Affect Age-Years American Amino Acids Antisense Oligonucleotides Biliary Biology COL1A1 gene Carbon Tetrachloride Cell Culture Techniques Cell physiology Cellular biology Choline Cicatrix Collagen Collagen Type I Complex Coupled Data Development Extracellular Matrix FDA approved Fatty Liver Fibrosis Fluorescent in Situ Hybridization Gene Expression Genes Genetic Transcription Genome Genomics Goals Health Hepatic Stellate Cell Hepatitis C Therapy High Fat Diet Human Incidence Injury Knowledge Lead Life Liver Liver Failure Liver Fibrosis Liver diseases Location Mediating Messenger RNA Mission Modeling Morbidity - disease rate Mus Myofibroblast Orthologous Gene Outcome Patients Population Precipitation Production Proteins Public Health RNA RNA Stability Regulation Reporter Research Risk Role Signal Transduction Site Testing Toxin Transcription Initiation Transforming Growth Factor beta United States National Institutes of Health Untranslated RNA Work base cell type chronic liver disease chronic liver injury experimental study frontier genome editing human disease improved in vivo in vivo Model innovation insight loss of function mortality non-alcoholic fatty liver disease novel novel strategies novel therapeutics prevent therapeutic target transcriptome sequencing

项目摘要

Project Summary Long noncoding (lnc) RNAs are a new frontier that we must explore to fully understand liver fibrosis. This class of noncoding RNAs has the same features as messenger (m) RNAs, but instead of encoding protein, lncRNAs operate to regulate cellular functions. To date, we understand the activity of only a small number of lncRNAs in hepatic stellate cells (HSCs), the primary cell type responsible for production of the fibrotic scar. The continued existence of this fundamental gap in our knowledge of lncRNA function in HSCs will impede our ability to develop new approaches to treat liver fibrosis. The long-term goal of this work is to understand how a new lncRNA that we have identified (TILAC, TGF-b-induced lncRNA Activating Collagen) regulates collagen (COL1A1) production in HSCs to control progression of liver fibrosis and use this insight to develop new approaches to treat patients with chronic liver disease. We identified TILAC through RNA-sequencing analysis in human HSCs. We find that it is induced by the fibrotic signal TGF-b, restricted in expression to HSCs and activated in human liver fibrosis. Depletion of TILAC leads to reduced expression of type I collagen, a primary component of the fibrotic scar. We have identified the mouse ortholog of TILAC by its conserved genomic location and find that this lncRNA is induced in murine HSCs with in vivo development of fibrosis. Depletion of TILAC in murine HSCs is also associated with decreased type I collagen expression. Our overall objective is to determine how TILAC regulates liver fibrosis. Out central hypothesis is that TILAC controls progression of fibrosis through regulation of COL1A1 expression in human and murine HSCs and can be targeted to inhibit fibrosis. The rationale for this proposal is that understanding how TILAC functions and developing a model to study TILAC activity in vivo will provide key insight into how lncRNAs regulate liver fibrosis. This proposal will also define a therapeutic target that is uniquely expressed in the liver in HSCs, and could be depleted without affecting other cell types in the liver. The central hypothesis will be tested by pursuing two specific aims: (1) Determine how TILAC regulates expression of COL1A1 in human HSCs and (2) Define the role of TILAC in liver fibrosis in vivo. In the first aim, loss-of-function analysis and rescue experiments coupled with RNA fluorescent in situ hybridization and lncRNA precipitation will determine how TILAC controls type I collagen expression and fibrosis. In the second aim, we will use TILAC- reporter and TILAC-deficient mice to define the cell types that express TILAC in vivo and determine how TILAC functions to regulate liver fibrosis. The proposed work is significant because understanding the mechanism by which lncRNAs regulate liver fibrosis will inspire transformative strategies to inhibit fibrosis through regulation of lncRNAs. It will also establish a path to identify and study lncRNAs in mice that are most relevant to patients with chronic liver disease. This work is innovative in the focus on lncRNAs to understand mechanism of liver fibrosis and how it applies genome editing approaches to disrupt and track lncRNA expression.

项目总结