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.

项目总结 摘要肺动脉高压(PAH)是一种罕见的慢性进行性肺血管疾病。 导致右室衰竭，最终导致死亡。尽管有可用的治疗方法和正在进行的研究努力， 目前尚无针对PAH或病理性血管重塑的根治疗法。当前 对染色质在PAH发病机制中的失调的了解仍然有限。Switch/蔗糖非 可发酵(SWI/SNF)染色质重塑复合体控制染色质对转录的可及性 以及共同监管机制。富含AT的交互式含结构域蛋白1a(ARID1A)是 SWI/SNF染色质重塑复合体在正常生理和疾病中发挥重要作用。内稳态 需要组蛋白甲基转移酶ARID1A和EZH2通过染色质介导的基因的平衡作用 表情。然而，ARID1A在多环芳烃中的作用仍未得到充分研究。鉴于涉及ARID1A的各种研究 作为一个重要的肿瘤抑制因子，本研究的目的是研究ARID1a和ARID1a的表达水平。 ARID1A和EZH2在肺血管平滑肌细胞(PASMCs)生长和生长中的关系 功能障碍。中心假说是ARID1a缺失会损害增强子介导的基因调控和驱动 PASMC在PAH中的异常生长通过染色质可及性改变和/或通过EZH2的DNA甲基化 (图1)。这一假设得到了ARID1A表达水平下调的初步数据的支持 PAH的人和动物模型。重要的是，使用shRNA耗尽ARID1A可增加PASMC的增殖 并增加EZH2的表达。因此，将通过追求以下两个具体的方法来检验该假设 目的：1)研究ARID1A在PASMC表型和基因表达调控中的作用 通过EZH2和靶向调控染色质的可及性，以及2)评估ARID1A特异性的效果 慢性缺氧下ARID1aSMC-/-小鼠SMC消融及EZH2抑制剂气管内给药的实验研究 和SUGEN条件。从这项提案中产生的数据将促进我们对 ARID1A在PASMC引起的肺血管疾病的表型中的作用及其治疗意义 对PAH的干预。