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.

项目概要 肺动脉高压（PAH）是一种罕见、慢性、进行性肺血管疾病，导致 导致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， 目前尚无针对 PAH 或病理性血管重塑的治愈方法。当前的 对 PAH 发病机制中染色质失调的了解仍然有限。开关/蔗糖非 可发酵 (SWI/SNF) 染色质重塑复合物控制染色质转录的可及性 和核心调节机制。富含 AT 的相互作用结构域蛋白 1a (ARID1a)，是 SWI/SNF 染色质重塑复合物在正常生理和疾病中发挥着重要作用。体内平衡 需要 ARID1a 和 EZH2（一种组蛋白甲基转移酶）通过染色质介导的基因实现平衡作用 表达。然而，ARID1a 在 PAH 中的作用仍未得到充分研究。鉴于涉及 ARID1a 的各种研究 作为一种重要的肿瘤抑制因子，本提案的目的是研究 ARID1a 和 ARID1a 的表达水平 ARID1A 和 EZH2 在肺血管平滑肌细胞 (PASMC) 生长中的联系 功能障碍。核心假设是 ARID1a 缺失会损害增强子介导的基因调控和驱动 通过 EZH2 改变染色质可及性和/或 DNA 甲基化，PASMC 在 PAH 中异常生长 （图1）。 ARID1a 表达水平下调的初步数据支持了这一假设。 PAH 的人类和动物模型。重要的是，使用 shRNA 消除 ARID1a 会增加 PASMC 增殖 并增加 EZH2 表达。因此，将通过以下两个具体的假设来检验该假设： 目标：1) 研究 ARID1a 在 PASMC 表型和基因表达调控中的新作用 通过 EZH2 和染色质可及性的靶向调节，以及 2) 评估 ARID1a 特异性的影响 慢性缺氧 ARID1aSMC-/- 小鼠 SMC 消融和 EZH2 抑制剂气管内递送 和苏根条件。该提案生成的数据将增进我们对以下角色的了解： ARID1a 在 PASMC 驱动的肺血管疾病表型中的作用及其治疗意义 PAH 的干预措施。