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.

项目总结