Regulation of Metabolic Programs for Host Tolerance to Inflammation

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PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program leading to the career development of Dr. Andrew Wang as an independent physician scientist. The principal investigator is a physician scientist with a PhD in Immunobiology who recently completed clinical fellowship training in Rheumatology. His career goal is to become an independent investigator studying tissue tolerance to inflammation. He proposes to expand his training in inflammation biology through an intensive training research experience under the mentorship of Dr. Ruslan Medzhitov, a pioneer and world leader with unparalleled intellectual and technical insight into tackling the complex biology of inflammation. In addition to intellectual grooming and hands-on training in Dr. Medzhitov's lab, a proposed rigorous series of didactic coursework and a carefully selected advisory committee comprised of physician-scientists with a broad range of expertise related to this project and with extensive experience in successfully fostering physician-scientist careers will equip him with the necessary skills to become a successful independent investigator. The research objective of this proposal is to understand how glucose metabolism regulates tissue tolerance to different types of inflammation. Preliminary data for this proposal reveals that nutritional supplementation enhances lethality in the Listeria model of bacterial sepsis while it protects against lethality in the flu model of viral sepsis. The causative component of food was determined to be glucose. Lethality was independent of the extent of systemic inflammation or pathogen burden. Findings were recapitulated in sterile models of bacterial and viral sepsis where therapeutic blockade of glucose metabolism with 2-deoxy glucose in the lipopolysaccharide model of bacterial sepsis lead to protection from mortality while therapeutic blockade of glucose metabolism in a Poly I:C model of viral sepsis lead to enhanced mortality, independent of the degree of inflammation. We hypothesized that different types of inflammation induced different metabolic states in order to coordinate appropriate activation of cytoprotective responses necessary for tissue protection from inflammatory damage. This proposal examines the role of ketone biology in mediating protection to bacterial inflammation and the role of the interferon alpha-mediated glucose-dependent unfolded protein response in viral inflammation. This proposal serves as a training vehicle for Dr. Andrew Wang to become an expert in inflammation, metabolic control, and tissue response to inflammation so that he can apply his expertise to the field of rheumatic diseases.