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.

项目概要 间质性肺疾病 (ILD) 包括特发性肺纤维化和其他形式的肺纤维化，是一种主要的疾病。 以及不断增加的医疗负担。虽然 FDA 批准的治疗方法可以限制纤维化 ILD 的进展，但它们并不能 从根本上改变这些疾病的病程。 ILD 纤维化进展的一个核心因素是 成纤维细胞持续激活至纤维化状态；而短暂的成纤维细胞激活会促进伤口 愈合、异常和长期成纤维细胞激活会促进纤维化 ECM 沉积并阻碍恢复 上皮和造血室中细胞稳态的影响。因此，了解成纤维细胞如何 被激活然后锁定在纤维化状态是开发更有效疗法的核心 对于纤维化 ILD。基于大量初步数据证明转录因子的关键作用 Runx1 在小鼠和人类纤维化肺组织中成纤维细胞激活和纤维化记忆中的作用，我们将测试 中心假设是，成纤维细胞获得并维持纤维生成激活的记忆，从而为它们做好准备 重复损伤后激活被放大，并且 Runx1 在这种激活和纤维形成中起着核心作用 记忆。我们建议通过三个具体目标来检验这一假设。在第一个目标中，我们将使用鼠标模型 确定纤维化过程中 Runx1 参与的位置、丰度和特定转录靶标 发起、决心和坚持。在第二个目标中，我们将测试是否有条件删除 Runx1 减轻纤维化和成纤维细胞记忆，减少重复博莱霉素损伤模型中的持续性纤维化， 并恢复间充质和其他肺室的稳态。在最终目标中我们将分析 人肺组织和新鲜分选的成纤维细胞来描述 Runx1 的参与、目标和功能效应 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作用的作用 和生化信号赋予纤维化记忆和 Runx1 激活，并将测试已建立的和 研究性疗法因其消除纤维化记忆的能力。这些研究将一起测试 Runx1 在小鼠模型和人体组织中纤维化细胞激活和记忆中的功能和调节， 潜在地确定纤维化 ILD 进展的新型靶向机制。