Pathological Interaction of Obesity and Sepsis: Role of Adipokines

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DESCRIPTION (provided by applicant): This career development award proposes a four-year training program for a board certified Critical Care physician scientist. Dr. Vidula Vachharajani, MD. Dr. Vachharajani has developed and uses several murine models of obesity to study endothelial dysfunction that occurs during sepsis. Obesity is known to exacerbate many immune and inflammatory responses, but the precise molecular and cellular mechanism(s) of the enhanced response is unknown. The preliminary data in obese mouse models suggest that the exaggerated inflammation in sepsis is related to an inflammatory phenotype associated with obesity. The objective of the research plan is to test the hypothesis that decreased adiponectin and increased P-selectin expression mediate the enhanced endothelial dysfunction seen in obese animals and humans with sepsis. The SPECIFIC AIMS to test the hypothesis are: (1) Using genetic modification, we will assess the effect of adiponectin on leukocyte and platelet adhesion, P-selectin expression, and blood-brain barrier function in cerebral microcirculation in lean and obese mice and on survival. Sepsis will be induced by cecal ligation puncture method. IA will assess the inflammatory response in adiponectin-deficient (Ad ko) lean and ob/ob mice. 1B will assess the inflammatory response in Ad over-expressing (Ad tg) lean and ob/ob mice with surgically induced sepsis. (2) We will use murine adiponectin (Ad) pre-treatment in lean ob/ob and diet induced obese (DIO) mice with surgically induced sepsis to assess the inflammatory response on leukocyte and platelet adhesion, P-selectin expression, blood-brain barrier function in the cerebral microcirculation and survival ofthe animals. The objective of the education plan is to further refine and develop research skills that complement Dr. Vachharajani's previous research experience. Her primary mentor, Charles McCall, MD, is Director ofthe WFU Translational Science Institute and Professor of Internal Medicine. He is an established physician scientist with over 35 years of research experience and has mentored over 40 trainees. Barbara Yoza, PhD, is Research Asst. Professor in the Dept. of Surgery and works closely with Dr. McCall as co-PI in directing his research laboratories. Dr. Kevin High, MD, MS, is Professor of Internal Medicine and will mentor Dr. Vachharajani's education (limited course of study in Molecular Medicine doctoral program) and professional (promotion both at the intramural and extramural level) development. RELEVANCE (See instructions): Increased morbidity and resource utilization in morbidly obese septic patients increases their cost of care further. Discoveries from this work may allow design of novel therapies to improve outcome of sepsis in obese humans. With rising number of obese-septic patients with increased morbidity, this proposal has great potential for substantial public health implications.