Brain G-alpha subunit protein mediated neural control of blood pressure

描述（由申请人提供）：在盐敏感受试者中，高盐摄入导致中枢交感神经流出增加、钠潴留和高血压。我们证明脑G1 i2亚基蛋白介导的交感神经抑制，心血管和肾脏排泄反应，中央GPCR激活和减轻高血压耐盐受试者。本申请将测试PVN G1 i2亚基蛋白门控通路在钠和水排泄的中枢神经控制和全身动脉血压调节中起关键作用的总体假设。PVN G1 i2蛋白响应于盐摄入量增加的内源性上调将增强内源性交感神经抑制机制以对抗盐敏感性高血压的发展，而PVN G1 i2蛋白内源性上调失败将加剧血压失调。将进行以下具体目的：具体目的1：确定1）脑G1 i2亚基蛋白门控通路介导对生理和药理学刺激的中枢诱发肾交感神经抑制反应，2）中枢G1 i2亚基蛋白内源性上调，作为一种反调节机制，以减弱Sprague-Dawley大鼠盐敏感性高血压的发展。具体目标二：在Sprague-Dawley大鼠中，将PVN确定为G1 i2亚单位蛋白内源性上调的特定脑部位，以增强肾交感神经抑制和利钠途径，从而维持液体和电解质稳态并对抗盐敏感性高血压的发展。具体目标3：为了确定1）响应于高盐摄入而上调PVN G112亚基蛋白的失败导致Dahl盐敏感性大鼠中内源性反调节肾交感神经抑制和利钠反应以及盐敏感性高血压的减弱，和2）PVN特异性基因治疗以过表达G1 i2-亚基蛋白将恢复肾交感神经抑制和利钠机制，并减弱Dahl盐敏感性高血压的发展。这些研究是国家心肺和血液研究所的核心使命，即促进心脏，肺和血液疾病的预防和治疗，并直接支持NHLBI战略计划，提高对健康和疾病的分子和生理基础的理解。具体目标1和2将使用寡脱氧核苷酸（ODN）来确定G1 i2蛋白在响应于急性药理学和生理学刺激的肾交感神经活性、液体和电解质稳态以及血压的中枢调节中的作用，从而消除脑，并且具体地PVN、G1 i2蛋白的影响（中枢12-肾上腺素受体和GABAB刺激，静脉内容量扩张）或Sprague-Dawley大鼠中慢性高盐摄入的综合生理刺激。具体目标3将定义PVN G1 i2蛋白的作用，通过ODN和慢病毒基因治疗方法，在盐敏感性高血压的达尔大鼠模型。这些创新的研究将进一步促进中枢神经系统自主调节和高血压研究领域，并可能导致高血压新的治疗靶点的确定。

DESCRIPTION (provided by applicant): In salt-sensitive subjects, high salt intake results in increased central sympathetic outflow, sodium retention and hypertension. We demonstrate brain G1i2-subunit proteins mediate the sympathoinhibitory, cardiovascular and renal excretory responses to central GPCR-activation and attenuate hypertension in salt-resistant subjects. This application will test the overall hypothesis that PVN G1i2-subunit protein-gated pathways play a critical role in the central neural control of sodium and water excretion and systemic arterial blood pressure regulation. Endogenous up-regulation of PVN G1i2 proteins in response to increased salt-intake will potentiate endogenous sympathoinhibitory mechanisms to counter the development of salt-sensitive hypertension whereas failure to endogenously up-regulate PVN G1i2 proteins will exacerbate blood pressure dysregulation. The following Specific Aims will be conducted: Specific Aim 1: To establish that 1) brain G1i2-subunit protein- gated pathways mediate centrally-evoked renal sympathoinhibitory responses to physiological and pharmacological stimuli and, 2) central G1i2-subunit proteins are endogenously up-regulated as a counter regulatory mechanism to attenuate the development of salt-sensitive hypertension in Sprague-Dawley rats. Specific Aim 2: To establish the PVN as a specific brain site in which G1i2-subunit proteins are endogenously up-regulated to potentiate renal sympathoinhibitory and natriuretic pathways to maintain fluid and electrolyte homeostasis and counter the development of salt-sensitive hypertension in Sprague-Dawley rats. Specific Aim 3: To establish that 1) failure to up-regulate PVN G1i2-subunit proteins, in response to high-salt intake, leads to attenuation of endogenous counter-regulatory renal sympathoinhibitory and natriuretic responses and salt- sensitive hypertension in Dahl salt-sensitive rats, and 2) PVN specific gene therapy to over express G1i2- subunit proteins will restore renal sympathoinhibitory and natriuretic mechanisms and attenuate the development of Dahl salt-sensitive hypertension. These studies are central to the mission of National Heart Lung and Blood Institute, which is to promote the prevention and treatment of heart, lung and blood disease, and directly support the NHLBI Strategic Plan of improving understanding of molecular and physiological basis of health and disease. Specific Aims 1 & 2 will remove the influence of brain, and specifically PVN, G1i2 proteins using oligodeoxynucleotides (ODN's) to determine the role(s) of G1i2 proteins in the central regulation of renal sympathetic nerve activity, fluid and electrolyte homeostasis, and blood pressure in response to acute pharmacological & physiological stimuli (central 12-adrenoceptor & GABAB stimulation, i.v. volume expansion) or the integrated physiological stimulus of chronic high salt-intake in Sprague-Dawley rats. Specific Aim 3 will define the role of PVN G1i2 proteins, via an ODN and lentiviral gene therapy approach, in the Dahl rat model of salt-sensitive hypertension. These innovative studies will further the fields of CNS autonomic regulation and hypertension research and potentially lead to the identification of new therapeutic targets for hypertension.