This application describes a program of research and education to enhance the applicant's skills that will permit an independent career in investigation of molecular mechanisms of cardiovascular metabolic diseases. The applicant has a background in clinical pharmacology, electrophysiology and biophysics acquired through previous training, but requires additional theory and methodology in molecular biology, gene transfer, confocal microscopy and bioinformatics. This proposal is tailored to provide training through execution of the scientific project under mentorship of a multidisciplinary advisory committee, as well as course work and seminars. The research component will investigate molecular mechanisms of body weight maintenance and obesity resistance. Obesity has become epidemic in western society with significant increase in cardiovascular morbidity and mortality, while available treatment options remain limited. Our preliminary data indicate that the ATP-sensitive potassium (KATP) channel regulates body weight through control of energy expenditure. However, understanding of the mechanism of this KATP channel-dependent control of body weight is lacking.The central hypothesis of this proposal is that KATP channels function as metabolic feedback effectors in striated muscles to limit calcium and sodium inward currents via action potential modulation, and thus control activity-related energy consumption. Under conditions of surplus calorie intake this promotes weight gain and obesity, while KATP channel deficit results in increased energy expenditure and protects against diet-induced obesity.
Aim #1 will resolve the mechanism of KATP channeldependent control of bodily energy expenditure, and Aim #2 will determine the signaling pathway for KATP channel workload-related expression control, as a tool to manipulate the channel function. Establishment of mechanisms underlying KATP channel regulation of bodily energy expenditure will identify potential therapeutic avenues for prevention of and targeted interventions for obesity management. In the short term, this scientific program in concert with the career development plan will alow the acquisition of skills and preliminary data necessary for an NIH R01 submission. In the long term, it will provide the foundation for the applicant to develop therapeutic strategies for bodily energy balance control, with direct ramification for cardiovascular disease conditions associated with obesity or energetic failure.
