LTBP2 regulation of fibrotic lung damage

LTBP2 对纤维化肺损伤的调节

基本信息

批准号：
10633230
负责人：
David M Ornitz
金额：
$ 19.46万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-02 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10633230
关键词：
Adult Affect Automobile Driving Binding Binding Proteins Binding Sites Biological Assay Biological Availability Biological Markers Bleomycin Cells Collagen Complex Data Development Diagnosis Diagnostic Disease Exposure to Extracellular Matrix Extracellular Matrix Proteins FBN1 FGF10 gene FGF2 gene Family Family member Fibroblasts Fibrosis Functional disorder Genes Genetic Genetic Models Goals Growth Growth Factor Health In Vitro Incidence Injury Knowledge LTBP2 gene Lung Lung diseases Mediating Mesenchymal Modeling Molecular Mus Myofibroblast Pathogenesis Pathogenicity Patients Peptides Population Prevention Primary Cell Cultures Production Proliferating Proteins Pulmonary Fibrosis Regulation Role Serum Signal Pathway Signal Transduction Site Study models Testing Time Tissues Transforming Growth Factor beta Wild Type Mouse cell type effective therapy epithelial repair experimental study fibrillin fibrotic lung fibrotic lung disease gene function idiopathic pulmonary fibrosis in vitro activity in vivo injured lung development lung injury lung repair member mouse genetics mouse model novel overexpression patient prognosis pulmonary function response response to injury single cell analysis single-cell RNA sequencing therapeutic target

项目摘要

Title: LTBP2 regulation of fibrotic lung damage Summary: Latent TGFβ Binding Protein 2 (LTBP2) is an extracellular matrix (ECM) protein. Unlike other proteins in the LTBP family, LTBP2 does not directly bind or regulate TGFβ activity. However, recent studies found that LTBP2 directly binds to FGF2. LTBP2 is highly expressed in the lung during development and during the pathogenesis of several pulmonary diseases including idiopathic pulmonary fibrosis (IPF). The elevated expression of LTBP2 in the lung and serum of patients diagnosed with IPF may be useful as a biomarker; however, whether it has a pathogenic role in IPF is not known. IPF is a disease that is characterized by cycles of pulmonary damage and repair that leads to the accumulation of fibrotic tissue in the lung. Over time, this fibrotic tissue reduces lung function and leads to poor patient prognosis. There are few effective treatments for IPF, as fibrotic damage is cumulative and permanent. Myofibroblast dysfunction has been identified as a major component of the lung damage observed in IPF. Fibroblasts and myofibroblasts are the main cells that express LTBP2 in the lungs of IPF patients, but the role of LTBP2 in pathogenic fibrosis is not known. In preliminary studies, we discovered that mice lacking Ltbp2 gene function develop considerably less pulmonary fibrosis than wild type mice when challenged with bleomycin, a common model for studying lung fibrosis. LTBP2 deficient lungs displayed lower collagen content, less extensive fibrosis, and less tissue destruction after exposure to bleomycin, suggesting that LTBP2 may be functionally involved in the pathogenic fibrotic response to lung injury. In our previous studies, we have shown that activation of FGF2 can decrease bleomycin-induced pulmonary fibrosis. We thus hypothesize that one function of LTBP2 could be to limit FGF2 bioavailability during the response to bleomycin-induced lung injury, and indirectly, through competition with other LTBPs for binding to fibrillin 1, enhance pro-fibrotic TGFβ activity. In this proposal, we use a combination of mouse genetic models and bleomycin-induced lung injury, primary cell culture, and single cell RNA sequencing, to test our hypothesis and identify underlying molecular and genetic mechanisms for LTBP2-extracellular matrix interactions and LTBP2-regulation of growth factor signaling in the pathogenesis of lung fibrosis in adult mice. The proposed experiments will also elucidate how key cell types contribute to fibrotic injury and will identify new genes that could be therapeutically targeted to reduce lung fibrosis in response to injury.

标题：LTBP2纤维化肺损伤的调节概括：潜在的TGFβ结合蛋白2（LTBP2）是细胞外基质（ECM）蛋白。与其他蛋白质不同 LTBP家族LTBP2不直接结合或调节TGFβ活性。但是，最近的研究发现LTBP2 直接与FGF2结合。 LTBP2在发育期间和发病机理期间在肺中高度表达包括特发性肺纤维化（IPF）在内的几种肺部疾病。 LTBP2的表达升高在诊断为IPF的患者的肺和血清中，可能是生物标志物的。但是，它是否有尚不清楚在IPF中的致病作用。 IPF是一种以肺部损伤和修复周期为特征的疾病，导致肺中纤维化组织的积累。随着时间的流逝，这种纤维化组织会降低肺功能，并导致较差病人提示。 IPF的有效治疗很少，因为纤维化损伤是累积和永久性的。肌纤维细胞功能障碍已被确定为IPF中观察到的肺损害的主要组成部分。成纤维细胞和成肌纤维细胞是在IPF患者肺中表达LTBP2的主要细胞，但是该作用致病性纤维化中的LTBP2的LTBP2尚不清楚。在初步研究中，我们发现缺乏LTBP2基因功能的小鼠仔细地发展较少当用博来霉素挑战时，肺纤维化比野生型小鼠是研究肺的常见模型纤维化。 LTBP2缺乏肺显示出较低的胶原蛋白含量，较少的纤维化和较少的组织暴露于博来霉素后的破坏，这表明LTBP2可能在功能上参与致病性对肺损伤的纤维化反应。在我们先前的研究中，我们已经表明FGF2的激活可以减少博来霉素诱导的肺纤维化。因此，我们假设LTBP2的一个函数可能是限制FGF2 在对博来霉素引起的肺损伤的反应过程中，并间接地通过与其他用于与纤维蛋白1结合的LTBP，增强了促纤维化TGFβ活性。在此提案中，我们结合了小鼠遗传模型和博来霉素诱导的肺损伤，主要细胞培养和单细胞RNA测序，以检验我们的假设并识别潜在的分子和遗传 LTBP2-细胞基质相互作用和LTBP2调节生长因子信号传导的机制成年小鼠肺纤维化的发病机理。提出的实验还将阐明关键细胞类型的方式有助于纤维化损伤，并将鉴定可以热靶向降低肺的新基因响应损伤的纤维化。