The role of the low density lipoprotein (LDL) receptor-related protein-1 (LRP-1) in pulmonary fibrosis

该建议旨在探讨多功能清道夫和信号受体LRP-1在肺纤维化中的致病作用，并在此基础上应用新的治疗策略。在第一个资助期，我们在纤维化条件下LRP-1的表达及其对肺成纤维细胞活性的影响方面获得了重要的见解。我们发现，在特发性肺纤维化(IPF)患者和各自的动物模型中，分离的肺成纤维细胞中LRP-1的表达显著下调。LRP-1缺乏显著影响成纤维细胞的功能，表现为黏附和迁移特性改变，促进增殖，增加产量，改变细胞外基质(ECM)蛋白的组成，以及减少ECM蛋白和止血因子的内吞作用。基于这些发现，下一个资金阶段的提案的目标是：(A)通过研究新产生的条件性细胞特异性LRP-1基因敲除小鼠，将LRP-1缺乏与体内肺纤维化的发展因果联系起来。(B)确定导致纤维化肺组织中lrp-1表达下调的因素，包括微RNA(S)。(C)评估LRP-1缺乏对转化生长因子-β1驱动的人肺成纤维细胞活性(增殖、细胞外基质产生、肌成纤维细胞分化)的影响。(D)确定LRP-1调节肺成纤维细胞黏附和迁移特性的分子机制。(E)应用不同的方法，通过全身/局部应用调节LRP-1表达的分子来预防和/或逆转肺纤维化动物模型的重塑过程。

This proposal aims to explore the pathogenic role of the multifunctional scavenger and signaling receptor LRP-1 in lung fibrosis, and to apply new therapeutic strategies based on these investigations. In the first funding period, we gained important insight in the expression of LRP-1 and its impact on lung fibroblast activities under fibrotic conditions. We found strong down-regulation of LRP-1 expression in isolated lung fibroblasts from Idiopathic Pulmonary Fibrosis (IPF) patients and in a respective animal model. LRP-1 deficiency markedly impacted fibroblast functions evidenced by altered adhesive and migratory properties, enhanced proliferation, increased production and altered composition of extracellular matrix (ECM) proteins, as well as diminished endocytosis of ECM proteins and haemostatic factors. Based on these findings the objectives of the proposal for the next funding period are (a) To causally link LRP-1 deficiency and the development of lung fibrosis in vivo by investigating newly generated conditional cell-specific LRP-1 knockout mice. (b) To identify factors, including microRNA(s), responsible for down-regulation of LRP-1 expression in fibrotic lungs. (c) To evaluate the consequences of LRP-1 deficiency for TGF-beta1-driven human lung fibroblast cellular activities (proliferation, ECM production, myofibroblast differentiation). (d) To identify the molecular mechanisms mediating LRP-1-regulated adhesive and migratory properties of lung fibroblasts. (e) To apply different approaches in order to prevent and/or reverse the remodelling process in animal models of lung fibrosis by systemic/local application of molecules modulating LRP-1 expression.