Urokinase plasminogen activator receptor associated protein and acute lung injury

描述（由申请人提供）：急性肺损伤（ALI）是一种常见综合征，死亡率高，在美国每年影响近20万危重患者。了解ALI的分子机制可能会导致未来潜在的治疗方法。本研究计划将重点关注uPARAP在ALI中的作用。 uPARAP是一种新发现的180 kDa跨膜蛋白，具有至少三种主要功能。首先，它是一种胶原蛋白受体，结合完整的胶原蛋白和片段，内化它们，并靶向它们进行溶酶体降解。其次，它结合uPAR（尿激酶纤溶酶原激活物受体），并可能降低uPA（尿激酶纤溶酶原激活物）激活。第三，它通过膜型1 - MMP（MT 1- MMP或MMP-14）依赖性途径抑制基质金属蛋白酶-2（MMP-2）活性。因此，uPARAP是一个独特的位置，影响重塑的细胞外基质，通过其调节细胞外和细胞内途径的胶原降解。我们的数据显示uPARAP在肺中高度表达，并且仅负责原代肺成纤维细胞中的胶原内化。由于uPARAP内化和降解胶原蛋白的能力及其在肺中的高表达，我们假设uPARAP -/-小鼠在气管内滴注博来霉素后将具有更大的纤维化。出乎意料的是，我们发现uPARAP -/-小鼠在纤维化发展之前具有显著的早期存活益处。此外，我们发现uPARAP -/-小鼠具有较少的肺泡出血和肺损伤。 本奖学金培训计划的目的是确定uPARAP -/-小鼠免受博来霉素诱导的急性肺损伤的保护机制。特异性目的1将通过嵌合小鼠的产生确定负责uPARAP -/-小鼠中保护的细胞类型。特异性目的2将确定uPARAP -/-小鼠是否由于胶原IV内化的丧失而改变基底膜功能。特异性目的3将确定uPA活性或MMP活性的变化是否导致uPARAP -/-小鼠免于肺损伤。这些目标将增加我们对uPARAP在急性肺损伤中意想不到的作用的理解。 公共卫生相关性：该提案将定义急性肺损伤修复的新的且不完全理解的机制的作用，急性肺损伤是一种具有高死亡率和高费用的疾病，在美国每年影响200，000人。它将帮助我们了解肺如何协调修复过程的几个组成部分。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a common syndrome with high mortality that affects nearly 200,000 critically ill people per year in the United States. Understanding the molecular mechanisms of ALI may lead to future potential therapies. This research proposal will focus on the role of uPARAP in ALI. uPARAP is a newly described 180 kDa transmembrane protein that has at least three primary functions. First, it is a collagen receptor that binds both intact collagen and fragments, internalizes them, and targets them for lysosomal degradation. Second, it binds uPAR (urokinase plasminogen activator receptor), and may decrease uPA (urokinase plasminogen activator) activation. Third, it suppresses matrix metalloproteinase-2 (MMP-2) activity through a membrane type 1 - MMP (MT1- MMP or MMP-14) dependent pathway. Thus, uPARAP is in a unique position to affect remodeling of the extracellular matrix through its regulation of extracellular and intracellular pathways of collagen degradation. Our data show that uPARAP is highly expressed in the lung, and is solely responsible for collagen internalization in primary lung fibroblasts. Due to uPARAP's capacity to internalize and degrade collagen, and its high expression in the lung, we hypothesized that uPARAP -/- mice will have greater fibrosis following intra-tracheal bleomycin instillation. Unexpectedly, we found that uPARAP -/- mice have a significant early survival benefit prior to the development of fibrosis. In addition, we found that uPARAP -/- mice had less alveolar hemorrhage with lung injury. The goal of this fellowship-training proposal is to determine the mechanism(s) of protection in uPARAP -/- mice from bleomycin-induced acute lung injury. Specific Aim 1 will determine the cell type responsible for protection in uPARAP -/- mice through the generation of chimeric mice. Specific Aim 2 will determine whether uPARAP -/- mice have altered basement membrane function due to loss of collagen IV internalization. Specific Aim 3 will determine whether changes in uPA activity or MMP activity result in protection from lung injury in uPARAP -/- mice. These aims will increase our understanding of the unexpected role of uPARAP in acute lung injury. PUBLIC HEALTH RELEVANCE: This proposal will define the role of a new and incompletely understood mechanism of repair of Acute Lung Injury, a disease with high mortality and expense that affects 200,000 people yearly in the United States. It will help us understand how the lung coordinates several components of the repair process.