Modulation of Lung Innate Immunity Prostaglandin E2

描述（由申请人提供）： 发展作为一个医生科学家的职业生涯需要广泛的培训，研究，教学和临床责任的适当平衡。 这项赠款提出了一个五年职业发展计划，其核心组成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，并从选择教师接受研究和职业监测。 这一职业发展建议进一步加强了密歇根大学的研究和指导的优秀环境。 该建议的重点是通过前列腺素（PG）E2（炎症的脂质介质）对肺泡巨噬细胞（AM）的免疫调节。 PGE 2通过连接四种不同的G蛋白偶联的E-前列腺素受体（EP 1、EP 2、EP 3和EP 4）来影响细胞功能的变化。 我们的初步数据表明，PGE 2抑制吞噬和杀死细菌病原体的AM通过EP 2受体介导的细胞内cAMP的增加。 目前尚不清楚的是cAMP下游抑制AM抗微生物功能的信号传导途径以及PGE 2（和单个EP受体亚型）对体内先天性肺免疫调节的贡献。 将进行体外和体内研究以解决以下具体目标：1）确定PKA依赖性和非依赖性途径在介导PGE 2对AM中FcR介导的吞噬作用的cAMP依赖性作用中的作用; 2）表征细菌性肺炎小鼠模型中PGE 2产生和细胞特异性EP受体表达的动力学; 3）使用药理学和遗传学方法确定内源性PGE 2在体内调节肺先天免疫中的作用以抑制或增强肺PGE 2产生;和4）使用四种EP受体亚型中每一种都有缺陷的转基因小鼠，定义单个EP受体对PGE 2调节的肺部炎症反应组分的影响。 成功完成提案中概述的研究将有助于确定宿主防御中相对研究不足的组成部分，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.