KATP channel regulation of bodily energy expenditure and weight maintenance

KATP 通道调节身体能量消耗和体重维持

• 批准号: 7666212
• 负责人: Leonid Zingman
• 金额: $ 12.74万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666212
• 关键词: Action Potentials; Adipose tissue; Advisory Committees; Arts; Bioinformatics; Biology; Biophysics; Body Weight; Body Weight decreased; Calcium; Cardiovascular Diseases; Cardiovascular system; Clinical Pharmacology; Complement; Confocal Microscopy; Consumption; Data; Deposition; Development Plans; Diabetes Mellitus; Diet; Disease; Eating; Education; Electrophysiology (science); Energy Intake; Energy Metabolism; Epidemic; Equilibrium; Failure; Feedback; Foundations; Gene Transfer; Genetic Transcription; Growth; Homeostasis; Image; Incidence; Intake; Intervention; Investigation; Ions; Iowa; Malignant Neoplasms; Mentorship; Metabolic; Metabolic Diseases; Methodology; Molecular; Molecular Biology; Morbidity - disease rate; Obesity; Obesity associated disease; Potassium; Prevention; Publishing; Regulation; Research; Research Personnel; Resistance; Resources; Role; Signal Pathway; Societies; Sodium; Striated Muscles; Techniques; Therapeutic; Training; Translations; United States National Institutes of Health; Universities; Weight Gain; Work; Workload; career; career development; energy balance; experience; innovation; mortality; multidisciplinary; novel; obesity management; prevent; programs; sensor; skill acquisition; skills; theories; tool; weight maintenance

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.

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，该计划将允许独立研究心血管代谢性疾病的分子机制。申请人具有通过以前的培训获得的临床药理学，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进行其他理论和方法。该建议旨在通过在多学科咨询委员会的指导下执行科学项目，课程工作和研讨会来量身定制培训。研究成分将研究体重维持和肥胖性耐药性的分子机制。肥胖症在西方社会中已成为流行病，心血管发病率和死亡率显着增加，而可用的治疗方案仍然有限。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，缺乏对这种KATP通道依赖性控制机制的理解。该提案的中心假设是，KATP通道在横纹肌肉中充当代谢反馈效应子，以通过动作电位模式限制钙和钠电流，从而限制与控制活性相关的能量消耗。在剩余卡路里摄入条件下，这会促进体重增加和肥胖，而KATP通道赤字会导致能量消耗增加，并防止饮食引起的肥胖症。 AIM＃1将解析KATP ChannelDeldent依赖人体能量消耗的机制，而AIM＃2将确定KATP通道工作负载相关的表达控制的信号传导途径，作为操纵通道函数的工具。建立KATP渠道规范身体能量消耗的机制将确定预防肥胖管理和有针对性干预措施的潜在治疗途径。在短期内，该科学计划与职业发展计划一致，将极大地获取NIH R01提交所需的技能和初步数据。从长远来看，它将为申请人提供基础，以制定身体能量平衡控制的治疗策略，并直接对与肥胖或能量衰竭相关的心血管疾病状况进行直接影响。