TRH in mediating the bradycardia of caloric restriction

描述(由申请人提供)： 卡路里摄入过多与心血管疾病之间的关系已经确立，与肥胖患者常见的心动过速有关的心血管疾病风险越来越受到关注。卡路里限制(CR)显著改善肥胖症患者的心率升高，同时降低非肥胖者的静息心率。这项建议的总体目标是阐明热量摄入减少导致心动过缓的潜在机制(S)。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小鼠热量限制的心动过缓中的作用。这项提议的第一个目的是直接测试这一假设，即交感神经系统和副交感神经系统流出的变化都是与热量限制相关的心动过缓的原因。这项提议的第二个目的是直接测试甲状腺激素变化在卡路里限制的心动过缓中不起作用的假设。这项建议的第三个也是最后一个目标是直接测试TRH信号的改变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关于下丘脑如何感知卡路里摄入量的知识与负责改变新陈代谢和心血管控制的效应通路结合起来。 心率测量将使用基于遥测的系统从小鼠身上进行，在该系统中，将EKG遥测仪放置在腹腔内，并将电导线放置在心脏的皮下。这项建议中使用的小鼠将缺乏完整的交感神经系统(DBH-/-)，缺乏到心脏的副交感神经系统(M2R-/-)，甲状腺功能低下，以及缺乏神经递质TRH(TRH-/-)。在卡路里限制期之前和期间，将测量静息和内在心率。

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.