KATP channel regulation of bodily energy expenditure and weight maintenance

描述（由申请人提供）：本申请描述了一项研究和教育计划，以提高申请人的技能，使其能够独立从事心血管代谢疾病分子机制的研究。申请人具有通过先前培训获得的临床药理学、电生理学和生物物理学背景，但需要分子生物学、基因转移、共聚焦显微镜和生物信息学方面的额外理论和方法。这项建议是专门为通过在多学科咨询委员会的指导下执行科学项目以及课程和研讨会提供培训而制定的。研究部分将研究体重维持和肥胖抵抗的分子机制。肥胖已成为西方社会的流行病，心血管疾病的发病率和死亡率显着增加，而可用的治疗选择仍然有限。我们的初步数据表明，ATP敏感性钾（KATP）通道通过控制能量消耗来调节体重。然而，这种KATP通道依赖性控制体重的机制尚不清楚，其核心假设是KATP通道在横纹肌中作为代谢反馈效应器，通过动作电位调节限制钙和钠内向电流，从而控制活动相关的能量消耗。在过量卡路里摄入的条件下，这促进体重增加和肥胖，而KATP通道缺陷导致能量消耗增加并防止饮食诱导的肥胖。目标#1将解决身体能量消耗的KATP通道依赖性控制的机制，目标#2将确定KATP通道工作负荷相关表达控制的信号传导途径，作为操纵通道功能的工具。建立KATP通道调节身体能量消耗的潜在机制将确定预防肥胖和针对肥胖管理的干预措施的潜在治疗途径。在短期内，这一科学计划与职业发展计划相结合，将允许获得NIH R01提交所需的技能和初步数据。从长远来看，它将为申请人开发用于身体能量平衡控制的治疗策略提供基础，直接衍生与肥胖或能量衰竭相关的心血管疾病状况。

DESCRIPTION (provided by applicant): 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.