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: 9274334
• 负责人: Richard David Wainford
• 金额: $ 13.72万
• 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/9274334
• 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; Disease; Diuretics; Electrolytes; Environment; Essential Hypertension; Excretory function; 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; Pharmacology; Physiological; Play; Program Development; Protein Subunits; Proteins; Receptor Activation; Recruitment Activity; Regulation; Research; Research Design; Research Institute; Resistance; Risk; Role; Signal Transduction; Site; Sodium; Sodium Chloride; Sprague-Dawley Rats; Stimulus; Teacher Professional Development; Techniques; Testing; Time; Training; Universities; Up-Regulation; Water; World Health Organization; attenuation; blood pressure regulation; career; career development; clinical diagnostics; design; dietary salt; disability; gene therapy; hemodynamics; hypertension treatment; innovation; medical schools; neuromechanism; neuroregulation; normotensive; novel therapeutics; paraventricular nucleus; pre-clinical; prevent; public health relevance; 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 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.

描述（由申请人提供）：在此K 02申请中，杰出且独立的R 01资助PI，已搬迁到波士顿大学医学院（BUSM）的世界级研究环境，以发展其独立研究生涯，将测试PVN G？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。 PVN G的内源性上调？i2蛋白在增加盐摄入量的反应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，而未能内源性上调PVN G？i2蛋白会加剧血压失调。 将进行以下特定目的（SA）：SA 1：确定1）脑G？i2-亚单位蛋白门控途径介导中枢诱发的肾交感神经抑制反应的生理和药理刺激，2）中央G？i2-亚基蛋白作为一种反调节机制内源性上调，以减轻Sprague-Dawley大鼠盐敏感性高血压的发展。 SA 2：确定下丘脑室旁核是一个特异的脑内部位，G？i2-亚基蛋白内源性上调以增强肾交感神经抑制和利钠途径，从而维持液体和电解质稳态并对抗Sprague-Dawley大鼠盐敏感性高血压的发展。 SA 3：确定1）未能上调PVN G？i2-亚单位蛋白，在高盐摄入，导致衰减内源性反调节肾交感神经抑制和利钠反应和盐敏感性高血压的Dahl盐敏感大鼠，和2）PVN特异性基因治疗，以过度表达G？i2-亚单位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。 新K 02 SA 4：确定室周器官作为激活内源性PVN G的关键中枢钠敏感机制？i2-亚单位蛋白门控肾交感神经抑制和利钠尿途径对抗盐敏感性高血压的发展 SA's1和SA' s2将消除大脑的影响，特别是PVN，G？i2蛋白使用寡脱氧核苷酸（ODN的），以确定G？i2蛋白在Sprague-Dawley大鼠对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学刺激的响应中对液体和电解质稳态和血压的中枢神经调节中的作用。SA 3将定义PVN G的角色？通过ODN和慢病毒基因治疗方法，在盐敏感性高血压Dahl大鼠模型中检测i2亚基蛋白。SA 4将整合室周器官在PVN G中的作用？i2蛋白介导的血压神经控制。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。