Uncovering the genomic regulatory network of myofibroblast differentiation in systemic sclerosis-associated interstitial lung disease

揭示系统性硬化症相关间质性肺疾病中肌成纤维细胞分化的基因组调控网络

• 批准号: 10523340
• 负责人: Eleanor Valenzi
• 金额: $ 16.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523340
• 关键词: Acute Respiratory Distress Syndrome; Affect; Autoimmune; Autoimmune Diseases; Automobile Driving; Binding; Binding Sites; Biological Assay; Cause of Death; Cell Nucleus; Cells; Chromatin; Clinical; Complex; Computational Molecular Biology; Critical Care; DNA; DNA Binding; Data; Deposition; Development; Disease; Effector Cell; Environment; Epigenetic Process; Etiology; Extracellular Matrix; Fibroblasts; Fibrosis; Fostering; Gases; Genes; Genetic Transcription; Genomics; Goals; Human; Hypersensitivity; Interstitial Lung Diseases; Investigation; K-Series Research Career Programs; Knowledge; Link; Lung; Medicine; Mentors; Myofibroblast; Pathogenesis; Pathogenicity; Patients; Phenotype; Physicians; Population; Process; Production; Publishing; Pulmonary Fibrosis; RNA; RUNX3 gene; Regulation; Regulator Genes; Regulatory Element; Research; Research Proposals; Rheumatism; Role; Sampling; Scientist; Small Nuclear RNA; Source; Structure of parenchyma of lung; Systemic Scleroderma; Transcription Factor 3; Transposase; United States; Universities; Work; XCL1 gene; analytical tool; career development; cell type; design; effective therapy; fibrotic lung disease; gain of function; gene regulatory network; genome-wide; improved; leadership development; mortality; multiple omics; novel therapeutics; nuclease; professor; programs; single-cell RNA sequencing; skills; skin fibrosis; therapeutic target; transcription factor; transcriptome; transcriptome sequencing

ABSTRACT This application is for a Mentored Clinical Scientist Research Career Development Award entitled “Uncovering the genomic regulatory network of myofibroblast differentiation in systemic sclerosis-associated interstitial lung disease”, submitted by Dr. Eleanor Valenzi, an Assistant Professor of Medicine within the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh. The short-term goals detailed in this submission are designed to help the applicant achieve her long-term objective of becoming an independent physician- scientist and leader in the field of autoimmune interstitial lung disease (ILD) research. These short-term goals include (1) advancing knowledge of computational and molecular biology (2) expansion of technical and analytic tools to effectively perform translational ILD research, and (3) development of leadership skills to obtain academic independence. This work will be completed in the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh, a rich research environment with a strong commitment to and proven track record of fostering the development of physician-scientists. The central objective of this research proposal is to investigate the gene regulatory networks driving myofibroblast differentiation in systemic sclerosis- associated interstitial lung disease (SSc-ILD), as myofibroblasts are the key effector cell in fibrosis and no treatments currently exist to target these cells. Interstitial lung disease is the leading cause of death in systemic sclerosis, the rheumatic disease with the highest case mortality. The applicant’s prior published work identified the transcriptome of the SSc-ILD pathogenic myofibroblasts in explanted lung tissues, however the specific gene regulatory networks driving differentiation of resident fibroblasts to pathogenic myofibroblasts remain unknown. Additional preliminary data implicates resident pulmonary fibroblasts as the primary source of myofibroblasts, and the RUNX2/3 transcription factors (TFs) as putative positive regulators of myofibroblast differentiation. The primary hypothesis is that RUNX2 and RUNX3, in association with specific composite motif TF partners, promote myofibroblast differentiation and the aberrant myofibroblast phenotype in SSc-ILD. With this proposal, the applicant will expand on her prior work with the following specific aims: (1) define the epigenetic and transcriptional programs essential to myofibroblast differentiation, (2) reconstruct the regulatory network of RUNX2/3 in myofibroblasts, and (3) determine the mechanism by which RUNX2/3 regulate the critical myofibroblast effector functions of extracellular matrix expression and contractility. This proposal will determine the SSc-ILD myofibroblast RUNX2/3 gene regulatory program and establish a pipeline for downstream investigation of the critical implicated transcription factors and the mechanisms by which they regulate the myofibroblast phenotype.

抽象的 本申请适用于指导临床科学家研究职业发展奖，题为“揭示 系统性硬化症相关间质性肺肌成纤维细胞分化的基因组调控网络 疾病”，由肺科医学助理教授 Eleanor Valenzi 博士提交， 匹兹堡大学的过敏和重症监护医学 本提交内容详细介绍了短期目标。 旨在帮助申请人实现成为一名独立医生的长期目标- 自身免疫性间质性肺疾病 (ILD) 研究领域的科学家和领导者。 包括 (1) 推进计算和分子生物学知识 (2) 扩展技术和分析 有效开展转化性 ILD 研究的工具，以及 (3) 发展领导技能以获得 这项工作将在肺科、过敏科和重症监护科完成。 匹兹堡大学医学部拥有丰富的研究环境，坚定的承诺和经过验证的 促进医师科学家发展的记录 本研究提案的中心目标。 是为了研究在系统性硬化症中驱动肌成纤维细胞分化的基因调控网络- 相关间质性肺疾病（SSc-ILD），因为肌成纤维细胞是纤维化的关键效应细胞，并且没有 目前存在针对这些细胞的治疗方法，间质性肺疾病是全身死亡的主要原因。 硬化症是病例死亡率最高的风湿性疾病。 外植肺组织中 SSc-ILD 致病性肌成纤维细胞的转录组，但特定基因 驱动常驻成纤维细胞分化为致病性肌成纤维细胞的调节网络仍然未知。 其他初步数据表明常驻肺成纤维细胞是肌成纤维细胞的主要来源， RUNX2/3 转录因子 (TF) 作为肌成纤维细胞分化的推定正调节因子。 主要假设是 RUNX2 和 RUNX3 与特定复合基序 TF 伙伴相关，促进 SSc-ILD 中的肌成纤维细胞分化和异常肌成纤维细胞表型。 申请人将扩展她之前的工作，以实现以下具体目标：（1）定义表观遗传和 肌成纤维细胞分化所必需的转录程序，（2）重建肌成纤维细胞的调控网络 肌成纤维细胞中的 RUNX2/3，以及 (3) 确定 RUNX2/3 调节关键细胞的机制 本提案将确定肌成纤维细胞的细胞外基质表达和收缩性效应功能。 SSc-ILD肌成纤维细胞RUNX2/3基因调控方案并建立下游管道 研究关键转录因子及其调节机制 肌成纤维细胞表型。