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

脑 G-α 亚基蛋白介导的血压神经控制

• 批准号: 8722013
• 负责人: Richard David Wainford
• 金额: $ 10.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722013
• 关键词: Acute; Adrenergic Receptor; Adult; Affect; Agonist; American; Animals; Antihypertensive Agents; Attenuated; Blood Pressure; Boston; Brain; Cardiovascular system; Cause of Death; Cessation of life; Chronic; Dahl Hypertensive Rats; Data; Development; Development Plans; Diagnostic; Diet; Disease; Diuretics; Electrolytes; Environment; Essential Hypertension; Excretory function; Faculty; Failure; Financial cost; Funding; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits; Grant; Guanabenz; Health; Homeostasis; Hypertension; Inbred Dahl Rats; Independent Scientist Award; Individual; Kidney; Lead; Lesion; Liquid substance; Mediating; Medical Education; Modeling; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Peer Review; Physiological; Play; Program Development; Protein Subunits; Proteins; Receptor Activation; Regulation; Research; Research Design; Research Institute; Resistance; Risk; Role; Signal Transduction; Site; Sodium; Sodium Chloride; Sprague-Dawley Rats; Stimulus; Techniques; Testing; Time; Training; Universities; Up-Regulation; Water; World Health Organization; attenuation; blood pressure regulation; career; career development; design; disability; gene therapy; hemodynamics; hypertension treatment; innovation; medical schools; neuromechanism; neuroregulation; normotensive; novel therapeutics; paraventricular nucleus; pre-clinical; prevent; relating to nervous system; response; salt intake; salt sensitive; salt sensitive hypertension; saluretic; stressor; therapeutic target

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 Gαi2-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 Gαi2 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 Gαi2 proteins will exacerbate blood pressure dysregulation. The following Specific Aims (SA) will be conducted: SA1: To establish that 1) brain Gαi2-subunit protein-gated pathways mediate centrally-evoked renal sympathoinhibitory responses to physiological and pharmacological stimuli and, 2) central Gαi2-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 Gαi2-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 Gαi2-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 Gαi2- 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 Gαi2-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, Gαi2 proteins using oligodeoxynucleotides (ODN's) to determine the role(s) of Gαi2 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 Gαi2-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 Gαi2 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.

描述（申请人提供）：在这个K 02申请中，杰出的和独立的R 01资助PI，谁已经搬迁到世界一流的研究环境在医学的波士顿大学学院（BUSM）发展他的独立研究生涯，将检验PVN Gαi2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。PVN Gαi2蛋白对盐摄入增加的响应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 Gαi2蛋白的内源性上调失败将加剧血压失调。将进行以下特定目的（SA）：SA 1：确定1）脑Gαi2-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Gαi2-亚基蛋白内源性上调作为一种反调节机制，以减轻Sprague-Dawley大鼠盐敏感性高血压的发展。SA2：在Sprague-Dawley大鼠中，将下丘脑PVN确定为一个特异性脑部位，其中Gαi2亚单位蛋白内源性上调，以增强肾交感神经抑制和利钠途径，从而维持体液和电解质稳态，并对抗盐敏感性高血压的发展。SA3：确定1）响应于高盐摄入而上调PVN Gα 12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，2）PVN特异性基因治疗Gαi2亚单位蛋白的过度表达将恢复肾交感神经抑制和利钠机制，并减轻Dahl盐的发展。敏感性高血压新K 02 SA 4：建立室周器官作为激活内源性PVN Gαi2亚单位蛋白门控肾交感神经抑制和利钠途径以对抗盐敏感性高血压发展的关键中枢钠敏感机制。SA's1和2将使用寡脱氧核苷酸（ODN's）消除脑，特别是PVN、Gαi2蛋白的影响，以确定Gαi2蛋白在Sprague-Dawley大鼠响应急性药理学和生理学刺激以及高饮食盐摄入的慢性综合生理刺激的液体和电解质稳态和血压的中枢神经调节中的作用。SA 3将通过ODN和慢病毒基因治疗方法确定PVN Gαi2亚基蛋白在盐敏感性高血压Dahl大鼠模型中的作用。SA 4将整合室周器官在PVN Gαi2蛋白介导的血压神经调控中的作用。在K 02职业发展计划期间，PI将在Cunningham博士（UNTHSC心血管研究所主任）的实验室接受培训，以获得AV 3V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。