权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic gene repression in pulmonary fibrosis

肺纤维化中的表观遗传基因抑制

基本信息

批准号：
9573741
负责人：
Giovanni Ligresti
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9573741
关键词：
Address Architecture Attention Attenuated Binding Bleomycin CREB1 gene Cells Chronic Cicatrix Connective Tissue Coupled Data Deposition Development Disease Disease Progression Epigenetic Process Fibroblasts Fibrosis G9a histone methyltransferase Gene Activation Gene Deletion Gene Expression Genes Genetic Transcription Histones Human In Vitro Inflammation Injury Intervention Investigation Label Lung Lung diseases Lysine Maintenance Mediating Mediator of activation protein Metabolic Methylation Methyltransferase Mitochondria Modeling Modification Mus Myofibroblast Normal tissue morphology Nucleic Acid Regulatory Sequences Organ failure Pathologic Pathologic Processes Pathway interactions Phase Process Promoter Regions Pulmonary Fibrosis RNA Interference RNA interference screen Reader Repression Resolution Role Stimulus Testing Therapeutic Therapeutic Intervention Time Tissues Transcription Repressor/Corepressor Transcriptional Regulation Uncertainty deep sequencing epigenetic regulation experimental study fibrogenesis gene repression genetic approach genome-wide human disease idiopathic pulmonary fibrosis in vivo indium-bleomycin inhibitor/antagonist insight knock-down loss of function lung injury mitochondrial dysfunction mitochondrial metabolism mortality mouse model novel overexpression programs research study small molecule targeted treatment tissue repair

项目摘要

PROJECT SUMMARY Pulmonary fibrosis represents an increasing cause of mortality worldwide and despite decades of investigation, considerable uncertainty exists as how this disease initiates and progresses. While multiple fibrogenic molecules have been found to drive aberrant matrix deposition, the mechanisms responsible for maintaining persistent and self-sustaining fibrogenesis are largely unknown. Targeting mechanisms that perpetuate the pathological state of fibroblasts during disease progression may serve as an attractive therapeutic strategy to halt lung fibrosis. The current proposal addresses the role of epigenetic gene repression in regulating fibroblast activation and lung fibrosis development. We will investigate the role of histone 3 lysine 9 methylation (H3K9me) as an important epigenetic modification that represses the transcription of genes essential to maintaining or returning lung fibroblasts to an anti-fibrotic or quiescent inactive state. Our preliminary data demonstrate that inhibition of H3K9 methylation by targeting the H3K9 methyltransferase G9a or the epigenetic reader CBX5 potently inhibits fibroblast activation by fibrogenic stimuli. Mechanistically, our data demonstrate that both G9a and CBX5 are directly involved in repressing PGC1, a master regulator of mitochondria metabolism significantly downregulated in diseased lung fibroblasts. Loss of PGC1 expression promotes fibroblast activation, while restoring PGC1 via epigenetic mechanisms reverses fibroblast activation. We will use loss of function strategies to target the epigenetic regulators CBX5 and G9a to investigate their mechanistic roles in switching fibroblasts between activated and quiescence states. Using mouse genetics approaches we will investigate the benefits of inhibiting H3K9 methylation in halting disease progression in bleomycin-induced lung fibrosis models. As our preliminary data strongly support an anti-fibrotic function for PGC1 during lung fibroblast activation in vitro, in this proposal we will further characterize its anti-fibrotic function and evaluate upstream and downstream transcriptional network that mediate its anti-fibrotic functions. Taken together, the proposed research studies will reveal critical epigenetic targets for therapeutic interventions aimed at halting or reversing the progression of pulmonary fibrosis.

项目总结