LTBP2 regulation of fibrotic lung damage

LTBP2对纤维化肺损伤的调节作用 摘要： 潜伏性转化生长因子β结合蛋白2是一种细胞外基质蛋白。与其他蛋白质不同 LTBP家族，LTbP2不直接结合或调节转化生长因子β活性。然而，最近的研究发现，LTBP2 直接与FGF2结合。在发育和发病过程中，LTBP2在肺组织中高表达。 包括特发性肺纤维化(IPF)在内的几种肺部疾病。LTBP2基因的高表达 在诊断为IPF的患者的肺和血清中作为生物标志物可能是有用的；然而，它是否具有 IPF的致病作用尚不清楚。 IPF是一种以肺损伤和修复的循环为特征的疾病，导致 肺内纤维组织积聚。随着时间的推移，这种纤维化组织会降低肺功能，导致肺功能不佳。 患者预后。IPF的有效治疗方法很少，因为纤维化损害是累积性的和永久性的。 肌成纤维细胞功能障碍已被认为是IPF肺损伤的主要组成部分。 成纤维细胞和肌成纤维细胞是IPF患者肺组织中表达LTBP2的主要细胞，但其在肺组织中的作用 LTBP2在病理性纤维化中的作用尚不清楚。 在初步研究中，我们发现缺乏Ltbp2基因功能的小鼠发育较少。 用博莱霉素(一种研究肺的常见模型)激发的野生型小鼠肺纤维化程度高于野生型小鼠 纤维化症。LTBP2缺乏的肺表现为较低的胶原含量、较少的广泛纤维化和较少的组织。 博莱霉素作用后的破坏，提示LTBP2可能在功能上参与了致病 肺损伤后的纤维化反应。在我们之前的研究中，我们已经表明FGF2的激活可以减少 博莱霉素性肺纤维化。因此，我们假设LTBP2的一个功能可能是限制FGF2 在博莱霉素诱导的肺损伤反应中的生物利用度，以及通过与 其他LTBP与纤维蛋白1结合，增强促纤维化转化生长因子β活性。 在这项建议中，我们使用了小鼠遗传模型和博莱霉素诱导的肺损伤的组合， 细胞培养和单细胞RNA测序，以验证我们的假设并确定潜在的分子和基因 LTBP2-细胞外基质相互作用机制及其对生长因子信号转导的调控 成年小鼠肺纤维化的发病机制。拟议的实验还将阐明关键细胞类型如何 有助于纤维化损伤，并将确定新的基因，可能是治疗的目标，以减少肺 对损伤的反应是纤维化。

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.