Modulation of Lung Innate Immunity by Prostaglandin E2

描述(由申请人提供)： 发展内科科学家的职业生涯需要广泛的培训，并适当平衡研究、教学和临床责任。这笔赠款提出了一项为期五年的职业发展计划，其核心部分是下文概述的研究项目。其他方面包括通过课程和实验室培训获得新的科学知识和研究技能，以及接受选定教员的研究和职业监测。密歇根大学现有的卓越的研究和指导环境进一步加强了这一职业发展建议。 这项建议的重点是前列腺素(PG)E2对肺泡巨噬细胞(AM)的免疫调节，前列腺素E2是炎症的脂质介质。PGE2通过连接四种不同的G蛋白偶联的E-前列腺素受体(EP1、EP2、EP3和EP4)来影响细胞功能的变化。我们的初步数据表明，PGE2通过EP2受体介导的细胞内cAMP增加，抑制AM对细菌病原体的吞噬和杀灭。目前尚不清楚的是cAMP下游抑制AM抗菌功能的信号通路，以及PGE2(和个别EP受体亚型)在体内调节肺固有免疫中的作用。体外和体内研究将针对以下具体目标：1)确定PKA依赖和非依赖的途径在介导PGE2对FCR介导的AM吞噬功能的cAMP依赖作用中的作用；2)在细菌性肺炎小鼠模型中表征PGE2产生的动力学和细胞特异性EP受体的表达；3)通过药理学和遗传学方法抑制或夸大肺PGE2的产生，以确定内源性PGE2在体内调节肺天然免疫中的作用；4)利用四种EP受体亚型均缺失的转基因小鼠，确定单个EP受体对PGE2调节的肺炎性反应成分的影响。 提案中概述的研究的成功完成将有助于确定宿主防御中一个相对研究较少的组成部分，并可能导致制定更好的肺炎预防和治疗策略。

DESCRIPTION (provided by applicant): Developing a career as a physician-scientist requires broad training, with a proper balance of research, teaching, and clinical responsibilities. This grant proposes a five-year career development plan, the central component of which is the research project outlined below. Other aspects include acquiring new scientific knowledge and research skills through coursework and laboratory training, and receiving research and career monitoring from select faculty. This career development proposal is further enhanced by the outstanding environment for research and mentoring that exists at the University of Michigan. This proposal focuses on the immunoregulation of the alveolar macrophage (AM) by prostaglandin (PG)E2, a lipid mediator of inflammation. PGE2 effects changes in cell functions through ligation of four distinct G-protein coupled E-prostanoid receptors (EP1, EP2, EP3 and EP4). Our preliminary data indicate that PGE2 inhibits both phagocytosis and killing of bacterial pathogens by AMs through an EP2 receptor-mediated increase in intracellular cAMP. What remain unclear are the signaling pathways downstream of cAMP that inhibit AM antimicrobial function and the contribution of PGE2 (and individual EP receptor subtypes) to the regulation of innate lung immunity in vivo. Both in vitro and in vivo studies will be performed to address the following specific aims: 1) determine the roles of PKA-dependent and -independent pathways in mediating the cAMP-dependent actions of PGE2 on FcR-mediated phagocytosis in AMs; 2) characterize the kinetics of PGE2 production and cell-specific EP receptor expression in a murine model of bacterial pneumonia; 3) determine the role of endogenous PGE2 in modulating pulmonary innate immunity in vivo using pharmacological and genetic approaches to inhibit or exaggerate lung PGE2 production; and 4) using transgenic mice deficient in each of the four EP receptor subtypes, define the influence of individual EP receptors on components of the pulmonary inflammatory response regulated by PGE2. Successful completion of the studies outlined in the proposal will help to define a relatively understudied component of host defense and may lead to the development of better preventive and therapeutic strategies against pneumonia.