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; 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 间质肺疾病（ILD），包括特发性和其他形式的肺纤维化代表主要 并增加医疗负担。虽然FDA批准的疗法限制了纤维化ILD的限制，但它们却不 从根本上改变了这些疾病的过程。 ILD中纤维化进展的主要元素是 将成纤维细胞持续激活至纤维化状态；而瞬态成纤维细胞激活促进伤口 愈合，异常和长时间的成纤维细胞激活促进纤维化ECM沉积并阻碍恢复 上皮和造血室中细胞稳态的。因此，了解成纤维细胞如何 被激活然后锁定在纤维态态中是开发更有效疗法的核心 用于纤维化ILD。基于广泛的初步数据，证明了转录因子的关键作用 Runx1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 成纤维细胞获得并维持纤维化激活的记忆的中心假设 重复损伤后的放大激活，该runx1在这种激活和纤维化中起着核心作用 记忆。我们建议以三个特定目标检验这一假设。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，丰度和特定的转录目标 启动，解决和持久性。在第二个目标中，我们将测试Runx1的条件删除是否有条件删除 减弱纤维化和成纤维细胞记忆，在反复的博来霉素损伤模型中减少持续性纤维化， 并恢复间充质和其他肺部室中的体内平衡状态。在最终目标中，我们将分析 人肺组织和新鲜的成纤维细胞以描绘RUNX1参与，靶标和功能效应 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的作用 以及赋予纤维化记忆和RUNX1激活的生化信号，并将测试已建立的和 研究性治疗药的擦除能力。这些研究将共同​​测试 Runx1在纤维化细胞激活和记忆中的功能和调节，在小鼠模型和人体组织中 潜在地识别出纤维化ILD进程的新型目标机制。