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

描述(由申请人提供)：在这份K02申请中，杰出的、独立资助的R01派已经搬迁到波士顿大学医学院(BUSM)的世界级研究环境中发展他的独立研究生涯，他将检验PVN G？I2亚单位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总体假设。盐摄入量增加时，内源性上调PVN G？I2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，而内源性上调PVN G？I2蛋白则加剧血压失调。SA1：建立1)脑G？I2-亚单位蛋白门控通路，介导对生理和药物刺激的中枢诱发的肾交感抑制反应；2)中枢G？I2-亚单位蛋白内源性上调，作为一种反向调节机制，以减轻盐敏感型高血压的发展。SA2：建立下丘脑PVN作为一个特定的脑部位，在此部位G？I2亚单位蛋白内源性上调，以加强肾交感神经抑制和钠尿途径，以维持水和电解质的动态平衡，并对抗盐敏感型高血压的发展。SA3：证实1)高盐摄入不能上调PVN G？I2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，并导致盐敏感型高血压；2)PVN特异性基因治疗过表达G？I2亚单位蛋白将恢复肾脏交感抑制和利钠机制，延缓Dahl盐敏感型高血压的发展。新的K02 SA4：建立一个关键的中枢钠感应机制，激活内源性PVN G？I2亚单位蛋白门控的肾交感神经抑制和钠尿通路，以对抗盐敏感型高血压的发展。SA‘s 1和2将去除脑，特别是PVN，G？I2蛋白的影响，利用寡脱氧核苷酸来确定G？I2蛋白在中枢神经调节液体和电解质平衡和血压中的作用(S)，以响应急性药物和生理刺激和高食盐摄入的慢性综合生理刺激。SA 3将通过ODN和慢病毒基因治疗方法，确定PVN G？I2亚单位蛋白在Dahl大鼠盐敏感型高血压模型中的作用。SA4将整合室周器官在PVN G？I2蛋白介导的血压神经调控中的作用。在K02职业发展计划期间，PI将在坎宁安博士(UNTHSC心血管研究所所长)的实验室接受培训，以获得AV3V病变的手术技术，并将参加BUSM医学教育学院发展计划办公室。

DESCRIPTION (provided by applicant): In this K02 application, the outstanding and independently R01 funded PI, who has relocated to the world class research environment at the Boston University School of Medicine (BUSM) to develop his independent research career, will test the overall hypothesis that PVN G?i2-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 G?i2 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 G?i2 proteins will exacerbate blood pressure dysregulation. The following Specific Aims (SA) will be conducted: SA1: To establish that 1) brain G?i2-subunit protein-gated pathways mediate centrally-evoked renal sympathoinhibitory responses to physiological and pharmacological stimuli and, 2) central G?i2-subunit proteins are endogenously up-regulated as a counter regulatory mechanism to attenuate the development of salt-sensitive hypertension in Sprague-Dawley rats. SA2: To establish the hypothalamic PVN as a specific brain site in which G?i2-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. SA3: To establish that 1) failure to up-regulate PVN G?i2-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 G?i2- subunit proteins will restore renal sympathoinhibitory and natriuretic mechanisms and attenuate the development of Dahl salt-sensitive hypertension. New K02 SA4: To establish the circumventricular organs as a critical central sodium sensing mechanism that activates endogenous PVN G?i2-subunit protein gated renal sympathoinhibitory and natriuretic pathways to counter the development of salt-sensitive hypertension. SA's1 & 2 will remove the influence of brain, and specifically PVN, G?i2 proteins using oligodeoxynucleotides (ODN's) to determine the role(s) of G?i2 proteins in the central neural regulation of fluid and electrolyte homeostasis and blood pressure in response to acute pharmacological & physiological stimuli and the chronic integrated physiological stimulus of high dietary salt-intake in Sprague-Dawley rats. SA 3 will define the role of PVN G?i2- subunit proteins, via an ODN and lentiviral gene therapy approach, in the Dahl rat model of salt-sensitive hypertension. SA4 will integrate the role of the circumventricular organs in PVN G?i2 protein mediated neural control of blood pressure. During the K02 Career Development plan the PI will train in the lab of Dr. Cunningham (Director UNTHSC Cardiovascular Research Institute) to acquire the surgical technique of AV3V lesions and will participate in the BUSM Office of Medical Education Faculty Development Program.