INTEGRATIVE NEUROBIOLOGY OF CARDIOVASCULAR REGULATION

描述(由申请人提供)： 本计划项目资助重点是心血管调节的综合神经生物学。现在已经是第36个年头了，它代表了爱荷华州心血管研究中心的主要科学重点。这种竞争性更新的力量是基于其高级领导层的凝聚力和协同作用，其概念和方法与新的研究人才的不断演变，以及从发现机制到将其转化为动物模型和人类的疾病状态的连续努力。流通自主控制的三个组成部分的功能整合体现在四个项目中。项目一：终板的神经加工和血压的长期调节(Johnson，Hay)将确定终板中枢神经元激活的分子决定因素-终板是启动神经体液驱动的关键调控部位。项目II-肾素-血管紧张素-醛固酮系统和肥胖-高血压的交感激活(Haynes，Mark，Rahmount i)将解决神经体液驱动的两个主要组成部分与心血管系统的耦合，即交感神经系统和肾脏-血管紧张素-醛固酮系统，作为肥胖人类高血压的决定因素。项目III-通过酸感离子通道进行的心血管感觉转导(Abboud，Benson，威尔士)将介绍参与压力感受器机械转导和化学感受器激活的分子传感器，这些分子感受器维持心血管系统的自主神经平衡，这对心血管疾病的生存至关重要。项目IV-在正常和心力衰竭状态(Chapleau，Anderson，Weiss)的压力感受器和交感神经元中的ROS信号将集中于ROS作为传入(压力感受器)和传出(交感)神经激活的生理和病理调节器，在新的心力衰竭模型中具有致命的因果关系。这五个项目中的分子靶标也反映了与功能靶标类似的整合水平。从心血管感觉器官的神经生物学(如压力化学受体；室周器官)；到神经体液信号分子(血管紧张素、醛固酮)；到跨膜受体、活性氧、分子转导和通道/通道蛋白。管理核心、矢量核心和动物模型核心已经为现有的项目提供了无价的服务。技术方法是最先进的，动物模型建立得很好，与病态条件和致命疾病(如心力衰竭、心肌梗死、高血压、动脉粥样硬化、自主神经功能障碍和肥胖)的相关性是直接的。公共线程创建了这个程序的智能结构，其中集成的结果将远远大于组件的总和。

DESCRIPTION (provided by applicant): This Program Project Grant focuses on Integrative Neurobiology of Cardiovascular Regulation. Now in its 36th year, it represents the major scientific emphasis of the Cardiovascular Research Center at Iowa. The strength of this competitive renewal is based on the cohesion and synergy of its senior leadership, its constant evolution in concepts and approaches with new investigative talent, and the continuum of the effort from discovery of mechanisms to their translation into disease states in animal models and humans. The functional integration of the three components of autonomic control of the circulation is represented in four projects. Project I: Neural Processing of the Lamina Terminalis and Long-Term Regulation of Blood Pressure (Johnson, Hay) will identify molecular determinants of activation of central neurons in the lamina terminalis - a key regulatory site for the initiation of neurohumoral drive. Project II - Renin-Angiotensin-Aldosterone System and Sympathetic Activation in Obesity-Hypertension (Haynes, Mark, Rahmouni) will address the coupling of the two major components of neurohumoral drive to the cardiovascular system, namely the sympathetic nervous system and the renal-angiotensin-aldosterone system in as determinants of hypertension in obese humans. Project III - Cardiovascular Sensory Transduction by Acid Sensing Ion Channels (Abboud, Benson, Welsh) will address the molecular sensors involved in mechanotransduction of baroreceptors and chemoreceptor activation that maintain an autonomic balance of the cardiovascular system that is essential for survival in cardiovascular disease. Project IV - ROS Signaling in Baroreceptor and Sympathetic Neurons in Normal and Heart Failure States (Chapleau, Anderson, Weiss) will focus on ROS as a physiologic and pathologic modulator of afferent (baroreceptors) and efferent (sympathetic) neural activation, with fatal causal implications in a new model of heart failure. The molecular targets in the five projects also reflect a level of integration similar to the functional ones. There is convergence from the neurobiology of cardiovascular sensory organs (e.g. baro-chemo-receptors; circumventricular organs); to neurohumoral signaling molecules (angiotensin, aldosterone); to transmembrane receptors, reactive oxygen species, molecular transducters, and channels/channel protein. The Administration Core, the Vector Core and Animal Models Core are already providing invaluable service to the existing programs. The technical approaches are state-of-the-art, the animal models are well established, and the relevance to morbid conditions and fatal diseases such as heart failure, myocardial infarction, hypertension, atherosclerosis, dysautonomia, and obesity is direct. Common threads create the intellectual fabric of this program where the integrated outcome will be far greater than the sum of the components.