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：
10432006
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432006
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 Lung fibrogenesis 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 fibrotic lung gene repression genetic approach genome-wide human disease idiopathic pulmonary fibrosis in vivo indium-bleomycin inhibitor 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.

项目概要肺纤维化是全世界日益严重的死亡原因，尽管经过了数十年的研究，这种疾病如何发生和进展存在相当大的不确定性。已发现分子可驱动异常基质沉积，该机制负责维持持续且自我维持的纤维发生在很大程度上是未知的。疾病进展过程中成纤维细胞的病理状态可能作为一种有吸引力的治疗策略目前的提案讨论了表观遗传基因抑制在调节成纤维细胞中的作用。我们将研究组蛋白 3 赖氨酸 9 甲基化的作用。（H3K9me）作为一种重要的表观遗传修饰，可抑制基因的转录维持或恢复肺成纤维细胞至抗纤维化或静止非活动状态。证明通过靶向 H3K9 甲基转移酶 G9a 或表观遗传抑制 H3K9 甲基化我们的数据表明，reader CBX5 可通过纤维形成刺激有效抑制成纤维细胞活化。 G9a 和 CBX5 都直接参与抑制 PGC1（线粒体的主要调节因子）患病肺成纤维细胞的代谢显着下调。成纤维细胞激活，同时通过表观遗传机制恢复 PGC1 可以逆转成纤维细胞激活。使用功能丧失策略来靶向表观遗传调节因子 CBX5 和 G9a，以研究它们的作用利用小鼠遗传学在成纤维细胞激活和静止状态之间切换的机制作用。我们将研究抑制 H3K9 甲基化在阻止疾病进展方面的益处我们的初步数据强烈支持博莱霉素诱导的肺纤维化模型的抗纤维化功能。 PGC1在体外肺成纤维细胞激活过程中，在本提案中我们将进一步表征其抗纤维化作用功能并评估介导其抗纤维化功能的上游和下游转录网络。总而言之，拟议的研究将揭示治疗的关键表观遗传靶点旨在阻止或逆转肺纤维化进展的干预措施。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aging Delays Lung Repair: Insights from Omics Analysis in Mice with Pulmonary Fibrosis.

DOI：
10.1165/rcmb.2023-0171ed
发表时间：
2023-10
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
通讯作者：

Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation.

DOI：
10.1038/s41419-021-04439-4
发表时间：
2021-12-17
期刊：
Cell death & disease
影响因子：
9
作者：
Ring NAR;Volpe MC;Stepišnik T;Mamolo MG;Panov P;Kocev D;Vodret S;Fortuna S;Calabretti A;Rehman M;Colliva A;Marchesan P;Camparini L;Marcuzzo T;Bussani R;Scarabellotto S;Confalonieri M;Pham TX;Ligresti G;Caporarello N;Loffredo FS;Zampieri D;Džeroski S;Zacchigna S
通讯作者：
Zacchigna S

Circular RNA Methylation: A New Twist in Lung Fibrosis.