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

描述(申请人提供)：在盐敏感的受试者中，高盐摄入会导致中枢交感神经流出增加、钠滞留和高血压。我们证明了脑G1I2亚单位蛋白介导了交感神经抑制、心血管和肾脏对中枢GPCR激活的排泄反应，并减轻了耐盐受试者的高血压。这一应用将检验PVN G1I2亚单位蛋白门控通路在中枢神经控制钠和水排泄和全身动脉血压调节中发挥关键作用的总体假设。盐摄入量增加时内源性上调PVN G1i2蛋白将增强内源性交感神经抑制机制以对抗盐敏感型高血压的发展，而不能内源性上调PVN G1i2蛋白将加剧血压调节失调。具体目标如下：1)建立脑G1I2亚单位蛋白门控通路，介导中枢诱发的肾交感神经抑制反应；2)中枢G1I2亚单位蛋白内源性上调，作为一种反向调节机制，减轻盐敏感型高血压大鼠的发展。具体目的2：建立下丘脑室旁核作为一个特定的脑部位，在此部位，G1I2亚单位蛋白内源性上调，以增强肾脏交感神经抑制和钠尿途径，维持液体和电解质的动态平衡，并对抗盐敏感型高血压的发展。具体目的3：证实：1)高盐摄入不能上调PVN G1I2亚单位蛋白，导致Dahl盐敏感大鼠内源性反向调节的肾交感抑制和利钠反应减弱，并导致盐敏感性高血压；2)PVN特异性基因治疗过表达G1I2亚单位蛋白将恢复肾交感神经抑制和钠尿机制，延缓Dahl盐敏感性高血压的发展。这些研究对国家心肺和血液研究所的使命至关重要，该使命旨在促进心肺和血液疾病的预防和治疗，并直接支持NHLBI战略计划，该战略计划旨在提高对健康和疾病的分子和生理基础的了解。特定的AIMS 1和2将消除脑，特别是PVN，G1I2蛋白的影响使用寡脱氧核苷酸(ODN)来确定G1I2蛋白在肾交感神经活动、液体和电解质平衡以及血压对急性药物和生理刺激(中枢12-肾上腺素受体和GAAB刺激)反应的中枢调节中的作用(S)。体积扩张)或慢性高盐摄入的综合生理刺激。具体目标3将通过ODN和慢病毒基因治疗方法，确定PVN G1i2蛋白在Dahl大鼠盐敏感型高血压模型中的作用。这些创新研究将进一步发展中枢神经系统自主调节和高血压研究领域，并有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.