KATP channel regulation of bodily energy expenditure and weight maintenance

描述(由申请人提供)：本申请描述了一项旨在提高申请人技能的研究和教育计划，该计划将使申请人能够独立从事心血管代谢疾病分子机制的研究工作。申请者具有临床药理学、电生理学和生物物理学的背景，但需要在分子生物学、基因转移、共聚焦显微镜和生物信息学方面的其他理论和方法。这项建议是为了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工作和研讨会来提供培训。研究部分将研究维持体重和抵抗肥胖的分子机制。肥胖已成为西方社会的流行病，心血管发病率和死亡率大幅上升，而可用的治疗选择仍然有限。我们的初步数据表明，ATP敏感钾(KATP)通道通过控制能量消耗来调节体重。然而，对这种依赖KATP通道控制体重的机制的了解还很少。这一假设的中心假设是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，从而控制与活动相关的能量消耗。在卡路里摄入过剩的情况下，这会促进体重增加和肥胖，而KATP通道缺陷会导致能量消耗增加，并防止饮食诱导的肥胖。目的1将解决KATP通道依赖的体能消耗控制机制，目标2将确定KATP通道工作负荷相关表达控制的信号通路，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机制将确定预防肥胖和有针对性地干预肥胖管理的潜在治疗途径。在短期内，这一科学计划与职业发展计划相结合，将有助于获得NIH R01提交所需的技能和初步数据。从长远来看，它将为申请者开发身体能量平衡控制的治疗策略提供基础，并直接衍生出与肥胖或精力衰竭相关的心血管疾病。

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.