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.
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