ARID1a and Chromatin Landscape in Pulmonary Vascular Disease

ARID1a 和肺血管疾病中的染色质景观

• 批准号: 10727052
• 负责人: Lahouaria HADRI
• 金额: $ 16.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10727052
• 关键词: ARID Domain; ARID1A gene; ATAC-seq; Ablation; Animal Model; Apoptosis; Blood Vessels; Cardiopulmonary; Cardiovascular system; Cells; Cessation of life; Chromatin; Chromatin Remodeling Factor; Chronic; Clinical; DNA Methylation; Data; Development; Disease; Dose; Down-Regulation; Enhancers; Epigenetic Process; Exhibits; Exposure to; Foundations; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; Homeostasis; Homologous Gene; Human; Hypoxia; Impairment; In Vitro; Knowledge; Life; Link; Lung; Malignant Neoplasms; Mediating; Medicine; Modeling; Molecular; Mus; Pathogenesis; Pathologic; Patients; Phenotype; Physiology; Pilot Projects; Play; Proteins; Public Health; Pulmonary arterial remodeling; Pulmonary artery structure; Rare Diseases; Regulation; Research; Research Priority; Research Support; Resistance; Role; Sampling; Site-Directed Mutagenesis; Smooth Muscle Myocytes; Structure; Sucrose; Testing; Therapeutic Intervention; Tissue-Specific Gene Expression; Tumor Suppressor Proteins; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Vascular resistance; cell growth; chromatin remodeling; curative treatments; epigenetic regulation; gain of function; histone methyltransferase; human disease; human model; hypertension treatment; improved; inhibitor; insight; new therapeutic target; novel; novel strategies; overexpression; pulmonary arterial hypertension; pulmonary vascular disorder; pulmonary vascular remodeling; right ventricular failure; small hairpin RNA; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; treatment strategy; vascular smooth muscle cell proliferation

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a rare, chronic, and progressive pulmonary vascular disease leading to right ventricle failure and ultimately to death. Despite the available treatments and ongoing research efforts, there is currently no curative treatment against PAH or the pathological vascular remodeling. Current understanding of the dysregulation of chromatin in PAH pathogenesis remains limited. The SWItch/Sucrose Non- Fermentable (SWI/SNF) chromatin remodeling complexes control accessibility of chromatin to transcriptional and coregulatory machineries. The AT-rich interactive domain-containing protein 1a (ARID1a), a subunit of the SWI/SNF chromatin-remodeling complex, plays important roles in normal physiology and diseases. Homeostasis requires balanced action of ARID1a and EZH2, a histone methyltransferase, through chromatin-mediated gene expression. Yet, the role of ARID1a in PAH remains understudied. Given the various studies implicating ARID1a as a critical tumor suppressor, the objective of this proposal is to investigate the expression level of ARID1a and the link between ARID1A and EZH2 in pulmonary vascular smooth muscle cells (PASMCs) growth and dysfunction. The central hypothesis is that ARID1a loss impairs enhancer-mediated gene regulation and drives aberrant growth of PASMC in PAH through altered chromatin accessibility and/or DNA methylation via EZH2 (Fig. 1). The hypothesis is supported by preliminary data of the downregulation of ARID1a expression level in human and animal models of PAH. Importantly, ARID1a depletion using shRNA increased PASMC proliferation and increased EZH2 expression. Hence, the hypothesis will be tested by pursuing the following two specific aims: 1) Investigate the emerging roles of ARID1a in PASMC phenotype and the regulation of gene expression through EZH2 and targeted modulation of chromatin accessibility, and 2) Evaluate the effects of ARID1a-specific ablation in SMC and the intratracheal delivery of EZH2 inhibitors in ARID1aSMC-/- mice exposed to chronic hypoxia and Sugen conditions. The data generated from this proposal will advance our knowledge about the role of ARID1a in the phenotype of PASMC-driven pulmonary vascular disease, with implications for therapeutic interventions in PAH.

项目摘要 肺动脉高压（PAH）是一种罕见的慢性进行性肺血管疾病， 右心室衰竭并最终死亡尽管有可用的治疗方法和正在进行的研究工作， 目前还没有针对PAH或病理性血管重塑的治愈性治疗。电流 对PAH发病机制中染色质失调的理解仍然有限。SWITCH/蔗糖非 可发酵（SWI/SNF）染色质重塑复合物控制染色质对转录的可及性。 和共同监管机制。富含AT的相互作用结构域蛋白1a（ARID 1a）是一个亚基， SWI/SNF染色质重塑复合物在正常生理和疾病中起重要作用。稳态 需要ARID 1a和EZH 2（一种组蛋白甲基转移酶）通过染色质介导的基因平衡作用 表情然而，ARID 1a在PAH中的作用仍未得到充分研究。鉴于各种研究表明ARID 1a 作为一种重要的肿瘤抑制因子，本研究的目的是研究ARID 1a的表达水平， ARID 1A和EZH 2在肺血管平滑肌细胞（PASMCs）生长中的联系， 功能障碍核心假设是ARID 1a缺失损害增强子介导的基因调控， 通过改变染色质可及性和/或通过EZH 2的DNA甲基化导致PAH中PASMC的异常生长 (Fig. 1）。这一假设得到了ARID 1a表达水平下调的初步数据的支持， PAH的人类和动物模型。重要的是，使用shRNA去除ARID 1a增加PASMC增殖 增加EZH 2的表达。因此，该假设将通过以下两个具体的 目的：1）研究ARID 1a在PASMC表型中的作用及其对基因表达的调控 通过EZH 2和染色质可及性的靶向调节，以及2）评估ARID 1a特异性 暴露于慢性缺氧的ARID 1aSMC-/-小鼠中SMC的消融和EZH 2抑制剂的腔内递送 Sugen条件从这一提议中产生的数据将促进我们对以下方面作用的认识： ARID 1a在PASMC驱动的肺血管疾病表型中的作用及其对治疗的意义 PAH的干预措施。