Mediators and Mechanisms of Innate Immunity in the Lung

描述(由申请人提供)： 在这项建议中，我们将探索一种新的天然宿主防御系统 心血管和肺脏系统。我们和其他人之前 证明补体过敏性毒素C5a和C3a在宿主中的作用 在肺部进行防御。我们现在已经鉴定出一种新的7-跨膜受体 这是第二个C5a受体。这种受体的信使核糖核酸除了 存在于粒细胞上，在心脏和肺中含量最丰富。而当 结合高亲和力的C5a，小鼠和人的受体带有突变 在与G蛋白偶联所必需的蛋白质区域。我们会 探索第二个C5a受体介导新信号的假设 性质独立于G蛋白，并可能作为一种调节 具有促炎特性的C5a受体。 第二个C5a受体的特征可能阐明新的途径 用于调节宿主防御和肺部炎症。此外， 完成这些目标将使人们能够进一步深入了解 炎症性肺病的合理治疗可能是可行的。

DESCRIPTION (provided by applicant): In this proposal, we will explore a novel system of innate host defense in the cardiovascular and pulmonary systems. We and others have previously demonstrated a role for the complement anaphylatoxins C5a and C3a in the host defense in the lung. We now have identified a novel 7-transmembrane receptor that is a second C5a receptor. The mRNA for this receptor, besides being present on granulocytes, is most abundant in the heart and lung. While binding C5a with high affinity, the receptor in mouse and man bears a mutation in the region of the protein essential for coupling to G proteins. We will explore the hypothesis that this second C5a receptor mediates novel signaling properties independent of G proteins, and may serve as a regulator of the pro-inflammatory characterized C5a receptor. The characterization of this second C5a receptor may elucidate novel pathways for regulation of host defense and inflammation in the lung. Further, completion of these aims will allow further insight into mechanisms by which rational therapies for inflammatory lung disease may be approached.