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Novel Roles for ADAM15 in Acute Lung Injury

ADAM15 在急性肺损伤中的新作用

基本信息

批准号：
7185955
负责人：
CAROLINE A OWEN
金额：
$ 40.38万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-12 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7185955
关键词：
Acute Lung Injury Adam15 gene Adult Respiratory Distress Syndrome Agonist Alveolar Apoptosis Apoptotic Binding Biochemistry Biology Blood capillaries Cell Adhesion Cell Surface Proteins Cell surface Cells Cellular biology Clathrin Cleaved cell Cytoplasm Cytoplasmic Granules Data Death Domain Disease Disintegrin Domain Disintegrins Employee Strikes Endopeptidases Enzymes Epithelial Epithelial Cells Extracellular Matrix Extracellular Matrix Proteins Family Family member Fibronectins Figs - dietary Gelatinase B Gene Targeting Generations Goals Half-Life Hypoxemia In Vitro Inflammatory Injury Integrins Interleukin-1 Receptors Lead Leukocytes Ligands Liquid substance Lung Lung Inflammation Matrix Metalloproteinases Mediating Mediator of activation protein Membrane Messenger RNA Metalloproteases Microspheres Modeling Molecular Morbidity - disease rate Mus Neutrophil Activation Oxidants Pathologic Pathology Pattern Peptide Hydrolases Physiological Play Predisposition Proteins Proteolysis Pulmonary Edema Rate Research Resistance Role Role playing therapy Sampling Site Surface TNFRSF6 gene TNFSF6 gene Testing Thinking Transmembrane Domain Tumor Necrosis Factor Receptor Vascular Endothelial Growth Factors Vascular Permeabilities Wild Type Mouse capillary cell injury cell type chemokine coated pit cytokine design in vivo inhibitor/antagonist injured insight lung injury macrophage man member migration mortality neutrophil novel receptor uptake

项目摘要

DESCRIPTION (provided by applicant): ADAM15 is a member of the ADAM family (proteinases with a disintegrin and a metalloproteinase domain). It is expressed by inflammatory cells, but little is known about its roles in the lung. Our studies of ADAM15-/- mice in a murine model of acute lung injury show that ADAM15 promotes PMN accumulation in the lung, and promotes alveolar capillary barrier injury. ADAM15 delays PMN apoptosis in the lung, and reduces macrophage uptake of apoptotic targets in vitro. ADAM15 is stored in PMN, and rapidly translocates to the PMN surface when cells are activated. ADAM15 degrades a lung extracellular matrix protein. We will investigate the mechanisms by which ADAM15 increases the lung PMN burden during ALI, and the cell biology and enzyme biochemistry of ADAM15 in PMN. We propose to pursue the following Specific Aims: Specific Aim 1. Investigate the mechanism by which ADAM15 promotes PMN survival in the lung: Aim 1A: We will test our hypothesis that ADAM15 increases the lung PMN burden by delaying PMN apoptosis by shedding of TNF receptor family members that regulate apoptosis. Aim 1B: We will test our hypothesis that ADAM15 also increases the lung PMN burden by inhibiting uptake of apoptotic PMN by lung macrophages. Specific Aim 2. Investigate the cell biology of ADAM15 in PMN. Aim 2A. We will test our hypothesis that ADAM15 is stored as a preformed proteinase within PMN cytoplasmic storage sites, and rapidly translocates to the cell surface when PMN are activated to degranulate. We will identify the storage sites for ADAM15 in PMN. Aim 2B. We will test our hypothesis that ADAM15 is subsequently internalized from the surface of activated PMN by a clathrin-dependent mechanism. Specific Aim 3. We will test our hypothesis that ADAM15 expressed on the surface of PMN is a TIMPresistant proteinase that cleaves matrix and non-matrix proteins to promote lung inflammation and injury. We hope that our studies will provide novel insights into the mechanisms by which ADAM 15 promotes neutrophilic lung inflammation and lung injury during ALI, and that in the long term, this will facilitate the design of new treatment strategies for ALI in man.

描述（由申请人提供）：ADAM 15是ADAM家族（具有去整合素和金属蛋白酶结构域的蛋白酶）的成员。它由炎性细胞表达，但对其在肺中的作用知之甚少。我们在急性肺损伤小鼠模型中对ADAM 15-/-小鼠的研究表明，ADAM 15促进肺中PMN积聚，并促进肺泡毛细血管屏障损伤。在体外，ADAM 15延迟肺中的PMN凋亡，并减少巨噬细胞对凋亡靶标的摄取。ADAM 15储存在PMN中，并且当细胞被激活时迅速易位到PMN表面。ADAM 15降解肺细胞外基质蛋白。我们将研究ADAM 15增加ALI时肺PMN负荷的机制，以及ADAM 15在PMN中的细胞生物学和酶生化。我们建议实现以下具体目标：具体目标1。研究ADAM 15促进肺内PMN存活的机制：目的1A：我们将验证我们的假设，即ADAM 15通过调节凋亡的TNF受体家族成员脱落来延迟PMN凋亡，从而增加肺PMN负荷。目的1B：我们将验证我们的假设，即ADAM 15也通过抑制肺巨噬细胞对凋亡PMN的摄取来增加肺PMN负荷。具体目标2。研究PMN中ADAM 15的细胞生物学。目标2A。我们将验证我们的假设，即ADAM 15作为一种预先形成的蛋白酶储存在PMN的胞质储存位点，并在PMN被激活去凋亡时迅速易位到细胞表面。我们将确定ADAM 15在PMN中的储存位点。目标2B我们将测试我们的假设，即ADAM 15随后从激活的PMN表面通过网格蛋白依赖性机制内化。具体目标3。我们将验证我们的假设，即在PMN表面表达的ADAM 15是一种TIMP抗性蛋白酶，其切割基质和非基质蛋白以促进肺炎症和损伤。我们希望我们的研究将为ADAM 15在ALI期间促进嗜酸性肺部炎症和肺损伤的机制提供新的见解，并且从长远来看，这将有助于设计人类ALI的新治疗策略。