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，旨在提高申请人的技能，从而使申请人能够在心血管代谢疾病的分子机制研究中独立从事职业生涯。申请人通过之前的培训获得了临床药理学、电生理学和生物物理学的背景，但需要额外的分子生物学、基因转移、共聚焦显微镜和生物信息学的理论和方法。该提案旨在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来提供培训。该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 敏感钾 (KATP) 通道通过控制能量消耗来调节体重。然而，对这种 KATP 通道依赖性体重控制机制的了解还很缺乏。该提案的中心假设是 KATP 通道在横纹肌中充当代谢反馈效应器，通过动作电位调节来限制钙和钠的内向电流，并且从而控制与活动相关的能源消耗。在热量摄入过剩的情况下，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，并防止饮食引起的肥胖。目标#1将解决KATP通道依赖性控制身体能量消耗的机制，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潜在机制将确定预防肥胖的潜在治疗途径和有针对性的肥胖管理干预措施。在短期内，该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，它将为申请人开发身体能量平衡控制的治疗策略提供基础，这对与肥胖或能量衰竭相关的心血管疾病有直接影响。