Novel Roles for ADAM15 in Acute Lung Injury

ADAM15是ADAM家族的成员(具有去整合素和金属蛋白酶结构域的蛋白酶)。 它由炎症细胞表达，但对其在肺中的作用知之甚少。我们对ADAM15的研究-/- 在小鼠急性肺损伤模型中，ADAM15促进了PMN在肺内的积聚， 促进肺泡毛细血管屏障损伤。ADAM15延缓肺内中性粒细胞凋亡，减少 巨噬细胞体外摄取凋亡靶标。ADAM15存储在PMN中，并快速转移到 当细胞被激活时，中性粒细胞表面。ADAM15可降解一种肺细胞外基质蛋白。我们会 探讨ADAM15在ALL期间增加肺PMN负荷的机制，以及细胞 ADAM15在中性粒细胞中的生物学和酶生化我们建议追求以下具体目标： 具体目的1.探讨ADAM15促进中性粒细胞在肺内存活的机制： 目的1A：我们将验证我们的假设，即ADAM15通过延迟PMN来增加肺PMN负荷 通过脱落调节细胞凋亡的肿瘤坏死因子受体家族成员而实现的细胞凋亡。 目的1B：我们将验证我们的假设，即ADAM15也通过抑制摄取而增加肺PMN负荷 肺巨噬细胞对中性粒细胞凋亡的影响。 具体目的2.研究ADAM15在PMN中的细胞生物学特性。 目标2 A。我们将验证我们的假设，即ADAM15作为预成型的蛋白酶存储在PMN中 细胞质存储位置，并在PMN被激活时迅速转移到细胞表面 脱颗粒。我们将在PMN中确定ADAM15的存储地点。 目标2B。我们将检验我们的假设，即ADAM15随后从激活的表面内化 PMN通过一种依赖于笼蛋白的机制。 具体目的3.我们将检验我们的假设，即在PMN表面表达的ADAM15是一种TIMP- 分解基质和非基质蛋白以促进肺部炎症和损伤的耐受性蛋白酶。 我们希望我们的研究将为ADAM15促进的机制提供新的见解 在ALI期间，中性粒细胞的肺部炎症和肺损伤，从长远来看，这将促进 设计治疗人类急性肺损伤的新策略。

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 All, 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 TIMP- resistant 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 ADAM15 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.