Fibrogenic activation and memory in the lung mesenchyme

肺间质的纤维化激活和记忆

• 批准号: 10558822
• 负责人: Daniel J. Tschumperlin
• 金额: $ 59.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558822
• 关键词: ATAC-seq; Atomic Force Microscopy; Attenuated; Binding; Biochemical; Biomechanics; Bleomycin; Cell Separation; Cells; ChIP-seq; Chromatin; Collagen; DNA Binding; Data; Data Set; Deposition; Development; Disease; Disease Progression; Elements; Epithelium; Exhibits; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Genes; Genetic Transcription; Hematopoietic; Homeostasis; Human; In Situ; Injury; Interstitial Lung Diseases; Label; Link; Location; Lung; Mechanics; Medical; Memory; Mesenchymal; Mesenchyme; Modeling; Mus; Play; Population; Publishing; Pulmonary Fibrosis; RNA Interference; Regulation; Resolution; Role; Signal Transduction; Slice; Sorting; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Transcriptional Regulation; Transforming Growth Factor beta; Translating; Work; effective therapy; fibrotic interstitial lung disease; fibrotic lung; genomic locus; human disease; human tissue; in vivo; knock-down; lung injury; mechanical signal; microscopic imaging; mouse model; novel; programs; protein expression; response; restoration; single-cell RNA sequencing; small molecule; transcription factor; transcriptome sequencing; wound healing

Project Summary Interstitial lung diseases (ILDs) including idiopathic and other forms of pulmonary fibrosis represent a major and growing medical burden. While FDA-approved therapeutics limit progression of fibrotic ILDs, they do not fundamentally alter the course of these diseases. A central element of fibrosis progression in ILDs is the persistent activation of fibroblasts to a fibrogenic state; whereas transient fibroblast activation promotes wound healing, aberrant and prolonged fibroblast activation promotes fibrotic ECM deposition and hinders restoration of cellular homeostasis in epithelial and hematopoietic compartments. Hence, understanding how fibroblasts become activated and then locked in fibrogenic states is central to the development more effective therapies for fibrotic ILDs. Based on extensive preliminary data demonstrating a key role for the transcription factor Runx1 in fibroblast activation and fibrogenic memory in mouse and human fibrotic lung tissue, we will test the central hypothesis that fibroblasts gain and maintain a memory of fibrogenic activation that primes them for amplified activation upon repeated injury, and that Runx1 plays a central role in this activation and fibrogenic memory. We propose to test this hypothesis in three specific aims. In the first aim we will use a mouse model to identify the location, abundance and specific transcriptional targets of Runx1 engagement during fibrosis initiation, resolution and persistence. In the second aim we will test whether conditional deletion of Runx1 attenuates fibrosis and fibroblast memory, diminishes persistent fibrosis in a repeated bleomycin injury model, and restores homeostatic states in mesenchymal and other lung compartments. In the final aim we will analyze human lung tissue and fresh sorted fibroblasts to delineate Runx1 engagement, targets and functional effects relevant to human disease. In both mouse and human tissue, we will seek to identify the role of mechanical and biochemical signals in conferring fibrogenic memory and Runx1 activation and will test established and investigational therapeutics for their capacity to erase fibrogenic memory. Together these studies will test the function and regulation of Runx1 in fibrogenic cell activation and memory in mouse models and human tissue, potentially identifying a novel targetable mechanism underlying fibrotic ILD progression.

项目摘要 包括特发性和其他形式的肺纤维化的间质性肺疾病（ILD）代表了肺纤维化的主要特征。 不断增长的医疗负担。虽然FDA批准的治疗方法限制了纤维化ILD的进展，但它们不能 从根本上改变这些疾病的发展过程。ILD中纤维化进展的核心要素是 成纤维细胞持续活化至纤维化状态;而瞬时成纤维细胞活化促进伤口愈合 愈合、异常和延长的成纤维细胞活化促进纤维化ECM沉积并阻碍恢复 上皮细胞和造血细胞的平衡。因此，了解成纤维细胞 被激活然后锁定在纤维化状态是发展更有效疗法的核心 治疗纤维化ILD基于大量的初步数据，证明了转录因子 Runx 1在小鼠和人类纤维化肺组织中的成纤维细胞激活和纤维化记忆中，我们将测试 一个中心假设，即成纤维细胞获得并保持纤维化激活的记忆， Runx 1在这种激活和纤维化中起着核心作用， 记忆我们建议在三个具体目标中检验这一假设。在第一个目标中，我们将使用小鼠模型 确定纤维化过程中Runx 1参与的位置、丰度和特异性转录靶点 发起、解决和坚持。在第二个目标中，我们将测试Runx 1的条件删除是否 减弱纤维化和成纤维细胞记忆，减少重复博来霉素损伤模型中的持续纤维化， 并恢复间充质和其它肺室中的稳态。最后，我们将分析 人肺组织和新鲜分选的成纤维细胞来描绘Runx 1接合、靶点和功能作用 与人类疾病有关。在小鼠和人体组织中，我们将寻求确定机械的作用， 和生化信号赋予纤维化记忆和Runx 1激活，并将测试建立和 研究性治疗剂，以消除纤维化记忆。这些研究将共同测试 Runx 1在小鼠模型和人组织中纤维化细胞活化和记忆中的功能和调节， 潜在地确定纤维化ILD进展的新靶向机制。