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: 8441295
• 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/8441295
• 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; public health relevance; relating to nervous system; response; salt intake; salt sensitive; 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）：在本次K02申请中，杰出的独立R01资助的PI，已经搬迁到波士顿大学医学院（BUSM）的世界一流的研究环境中发展他的独立研究生涯，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和全身动脉血压调节中起关键作用。内源性PVN G？i2蛋白对盐摄入量增加的反应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 G？I2蛋白会加剧血压失调。以下具体目标（SA）将进行：SA1：建立1)大脑G？2亚基蛋白门控通路介导中央诱发的肾交感神经抑制反应，以应对生理和药理学刺激；在Sprague-Dawley大鼠中，i2亚基蛋白作为一种反调控机制被内源性上调，以减轻盐敏感性高血压的发展。目的：建立下丘脑PVN作为G？在Sprague-Dawley大鼠中，i2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。SA3：为了证明1)PVN G上调失败？i2亚基蛋白对高盐摄入的反应导致内源性反调节性肾交感神经抑制和利钠反应的衰减，导致Dahl盐敏感大鼠盐敏感性高血压；2)PVN特异性基因治疗过表达G？i2-亚基蛋白将恢复肾脏交感抑制和利钠机制，并减轻Dahl盐敏感性高血压的发展。新的K02 SA4：建立心室周围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抑制和尿钠途径对抗盐敏感性高血压的发展。SA的1和2将消除大脑的影响，特别是PVN， G？利用寡脱氧核苷酸（ODN's）来确定G？i2蛋白在Sprague-Dawley大鼠对急性药理学和生理刺激及高盐饮食慢性综合生理刺激下中枢神经调节体液和电解质稳态和血压中的作用SA 3将定义PVN G的作用。i2-亚基蛋白，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。SA4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K02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AV3V病变的手术技术，并将参加BUSM医学教育教师发展计划办公室。