TRH in mediating the bradycardia of caloric restriction

TRH 介导热量限制引起的心动过缓

• 批准号: 6953862
• 负责人: STEVEN John SWOAP
• 金额: $ 20.08万
• 依托单位: WILLIAMS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953862
• 关键词: biological signal transduction; body temperature; bradycardia; caloric dietary content; dietary restriction; electrocardiography; genetically modified animals; heart rate; hormone regulation /control mechanism; hypothyroidism; laboratory mouse; laboratory rat; longitudinal animal study; neuroregulation; parasympathetic nervous system; sympathetic nervous system; telemetry; thyroid hormones; thyrotropin releasing hormone

DESCRIPTION (provided by applicant): The relationship between excess caloric intake and cardiovascular disease is well established, with increasing attention being paid to the cardiovascular disease risk linked to the tachycardia that is commonly seen in obese patients. Caloric restriction (CR) significantly ameliorates the elevated heart rate (HR) seen in obesity, as well as lowering resting HR in non-obese humans. The overall goal of this proposal is to elucidate the underlying mechanism(s) of the bradycardia induced by the reduction of caloric intake. The following specific aims will address important questions in cardiovascular biology concerning the roles of thyrotropin releasing hormone, thyroid hormones, the parasympathetic nervous system, and the sympathetic nervous system in the bradycardia of caloric restriction in mice. The first aim of this proposal is to directly test the hypothesis that alterations in both the sympathetic nervous system and parasympathetic nervous system outflow are responsible for the bradycardia associated with caloric restriction. The second aim of this proposal is to directly test the hypothesis that alterations in thyroid hormones do not play a role in the bradycardia of caloric restriction. The third and final aim of this proposal is to directly test the hypothesis that a change in TRH signaling is necessary for the bradycardia of caloric restriction. Successful completion of these goals will allow us to integrate what is currently known about how caloric intake is sensed in the hypothalamus with the effector pathways responsible for altered metabolism and cardiovascular control. HR measurements will be taken from mice using a telemetry-based system, where an EKG telemeter is placed in the abdominal cavity with electrical leads placed subcutaneously across the heart. The mice to be used in this proposal will be lacking an intact sympathetic nervous system (Dbh-/-), lacking parasympathetic nervous system to the heart (M2R-/-), hypothyroid, and lacking the neurotransmitter, TRH (Trh-/-). Resting and intrinsic HRs will be measured before and during a caloric restriction period.

描述（由申请人提供）： 过量热量摄入与心血管疾病之间的关系已经得到了很好的确立，越来越多的关注与肥胖患者中常见的心动过速相关的心血管疾病风险。热量限制（CR）显著改善肥胖症患者的心率（HR）升高，并降低非肥胖人群的静息HR。本提案的总体目标是阐明热量摄入减少引起心动过缓的潜在机制。以下具体目标将解决心血管生物学中的重要问题，涉及促甲状腺激素释放激素、甲状腺激素、副交感神经系统和交感神经系统在热量限制的小鼠心动过缓中的作用。该建议的第一个目的是直接检验交感神经系统和副交感神经系统流出的改变是与热量限制相关的心动过缓的原因这一假设。该建议的第二个目的是直接检验甲状腺激素的改变在热量限制的心动过缓中不起作用的假设。该提议的第三个也是最后一个目的是直接检验TRH信号传导的变化对于热量限制的心动过缓是必要的这一假设。这些目标的成功完成将使我们能够将目前已知的下丘脑如何感知热量摄入与负责改变代谢和心血管控制的效应器通路相结合。 将使用基于遥测的系统从小鼠中进行HR测量，其中将EKG遥测仪放置在腹腔中，将电导线皮下放置在心脏上。用于该提议的小鼠将缺乏完整的交感神经系统（Dbh-/-），缺乏心脏的副交感神经系统（M2 R-/-），甲状腺功能减退，并且缺乏神经递质TRH（Trh-/-）。将在热量限制期之前和期间测量静息和固有HR。

项目成果

A single bout of torpor in mice protects memory processes.

• DOI: 10.1016/j.physbeh.2009.02.013
• 发表时间: 2009-04-20
• 期刊: PHYSIOLOGY & BEHAVIOR
• 影响因子: 2.9
• 作者: Nowakowski, Sarah G.;Swoap, Steven J.;Sandstrom, Noah J.
• 通讯作者: Sandstrom, Noah J.

The pharmacology and molecular mechanisms underlying temperature regulation and torpor.

• DOI: 10.1016/j.bcp.2008.06.017
• 发表时间: 2008-10-01
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Swoap, Steven J.

Norepinephrine controls both torpor initiation and emergence via distinct mechanisms in the mouse.

• DOI: 10.1371/journal.pone.0004038
• 发表时间: 2008
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Swoap SJ;Weinshenker D
• 通讯作者: Weinshenker D

Oxyntomodulin increases intrinsic heart rate through the glucagon receptor.

• DOI: 10.1002/phy2.112
• 发表时间: 2013-10
• 期刊: PHYSIOLOGICAL REPORTS
• 影响因子: 2.5
• 作者: Mukharji, Auyon;Drucker, Daniel J;Charron, Maureen J;Swoap, Steven J
• 通讯作者: Swoap, Steven J

Cardiovascular changes during daily torpor in the laboratory mouse.

• DOI: 10.1152/ajpregu.00131.2009
• 发表时间: 2009-09-01
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Swoap, Steven J;Gutilla, Margaret J
• 通讯作者: Gutilla, Margaret J