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：
10020431
负责人：
Giovanni Ligresti
金额：
$ 41.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020431
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 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 genetics 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.

项目摘要肺纤维化代表了全球死亡率的越来越多的原因，并且是研究数十年来的造成死亡的原因，随着这种疾病如何发起和进展，存在很大的不确定性。而多纤维化已经发现分子驱动异常基质沉积，该机制负责维持持续和自我维持的纤维发生在很大程度上是未知的。目标机制使疾病进展过程中成纤维细胞的病理状态可能是一种有吸引力的治疗策略停止肺纤维化。当前的建议涉及表观遗传基因表达在调节成纤维细胞中的作用激活和肺纤维化发展。我们将研究组蛋白3赖氨酸9甲基化的作用（H3K9Me）作为重要的表观遗传修饰，反映了基因的转录将肺成纤维细胞保持或返回到抗纤维化或静止状态。我们的初步数据证明通过靶向H3K9甲基转移酶G9A或表观遗传学来抑制H3K9甲基化读取器CBX5可能会通过纤维生成刺激抑制成纤维细胞激活。从机械上讲，我们的数据证明了 G9A和CBX5都直接参与了线粒体的主要调节剂PGC1 新陈代谢在肺成纤维细胞中显着下调。 PGC1表达的丧失促进成纤维细胞激活，而通过表观遗传机制恢复PGC1会逆转成纤维细胞激活。我们将利用功能策略的丧失来针对表观遗传调节剂CBX5和G9A调查其在激活状态和静止状态之间切换成纤维细胞中的机械作用。使用小鼠遗传学方法我们将研究抑制H3K9甲基化在停止疾病进展中的好处博来霉素诱导的肺纤维化模型。因为我们的初步数据强烈支持抗纤维化功能 PGC1在体外肺成纤维细胞激活期间，在此提案中，我们将进一步表征其抗纤维化功能并评估介导其抗纤维化功能的上游和下游转录网络。综上所述，拟议的研究将揭示治疗的关键表观遗传靶标旨在停止或逆转肺纤维化进展的干预措施。