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

描述（由申请人提供）：在盐敏感的受试者中，高盐摄入导致中枢性交感神经流出增加，钠潴留和高血压。我们证明脑g1i2亚基蛋白介导交感抑制，心血管和肾脏排泄反应中枢gpcr激活和减轻高血压耐盐受试者。该应用将验证PVN g1i2亚基蛋白门控通路在中枢神经控制钠和水排泄以及全身动脉血压调节中发挥关键作用的整体假设。内源性上调PVN G1i2蛋白以响应盐摄入量的增加，将增强内源性交感病理抑制机制，以对抗盐敏感性高血压的发展，而内源性上调PVN G1i2蛋白将加剧血压失调。具体目的1：确立1)脑g1i2亚基蛋白门控通路介导中央诱发的肾对生理和药理学刺激的交感抑制反应；2)中枢g1i2亚基蛋白作为一种反调控机制内源性上调，以减轻Sprague-Dawley大鼠盐敏感性高血压的发生。特异性目的2：在Sprague-Dawley大鼠中，建立PVN作为一个特定的脑部位，g1i2亚基蛋白内源性上调，增强肾脏交感神经抑制和尿钠途径，以维持液体和电解质稳态，并对抗盐敏感性高血压的发展。特异性目的3：确定1)高盐摄入导致PVN G1i2亚基蛋白上调失败，导致Dahl盐敏感大鼠内源性反调节性肾交感神经抑制和利钠反应的减弱和盐敏感性高血压；2)PVN特异性基因治疗过度表达G1i2亚基蛋白将恢复肾脏交感神经抑制和利钠机制，减轻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任务，该研究所旨在促进心脏、肺和血液疾病的预防和治疗，并直接支持NHLBI战略计划，以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将消除大脑，特别是PVN， G1i2蛋白的影响，使用寡脱氧核苷酸（ODN）来确定G1i2蛋白在急性药理学和生理刺激（中枢12-肾上腺素能受体和GABAB刺激）下对肾交感神经活动、液体和电解质稳态和血压的中枢调节中的作用。Sprague-Dawley大鼠慢性高盐摄入的综合生理刺激。特异性Aim 3将通过ODN和慢病毒基因治疗方法确定PVN G1i2蛋白在盐敏感性高血压Dahl大鼠模型中的作用。这些创新研究将进一步推动中枢神经系统自主调节和高血压研究领域的发展，并有可能导致发现新的高血压治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Hypertension, a condition affecting 1 in 3 US adults, caused approximately 326,000 US deaths in 2006 and is predicted to be the leading global cause of death by the year 2020. This project will establish why certain individuals are resistant to increases in blood pressure caused by dietary salt intake and will potentially lead to the development of new therapeutics to prevent the development of salt-sensitive hypertension.