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.
Hypertension, a condition affecting 1 in 3 US adults, caused approximately 347,689 US deaths in 2008 and is predicted by the World Health Organization to be the leading global cause of death by the year 2020. This project, which will significantly enhance the independent research career of the PI, will establish why certain individuals are resistant to increases in blood pressure caused by dietary salt intake and, as noted by the reviewers of the funded R01 component, has great potential to lead to the development of new therapeutics designed to prevent the development of salt-sensitive hypertension.
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