Hypertension is a widespread health problem and a major risk factor for cardiovascular disease, the leading cause of death in the USA. Of particular concern is drug-resistant hypertension, which is accompanied by enhanced sympathetic nervous system activity, indicating that the increased blood pressure arises from neurogenic origins. Nearly one-third of hypertensive patients fall into this category for which there are no effective medications and determining strategies to treat or prevent neurogenic hypertension has great significance for public health. My overall career goal is to become an independent academic scientist that studies impairments in neural circuits that elicit neurogenic hypertension, as well as the development of therapeutics that alleviate these impairments. The expectation is that my research will contribute substantively to the understanding of the causes of neurogenic hypertension and to the development of therapeutics used to treat it. The activities proposed in this application are designed to facilitate reaching tis goal and will investigate a novel therapeutic target for neurogenic hypertension - angiotensin type-2 receptors (AT2R) expressed within the brain. The experiments test the overall hypothesis that activation of AT2R on neurons that project to the paraventricular nucleus of the hypothalamus (PVN; a brain region important for controlling sympathetic outflow and blood pressure) negatively-regulate blood pressure, potentially making activation of AT2R a suitable target for antihypertensive medications. My graduate training used laboratory rodents to examine how angiotensin-II, a peptide heavily implicated in the development of hypertension and cardiovascular disease, influenced the neural control of body weight and glucose metabolism. This line of research introduced me to the central pathways that were sensitive to angiotensin-II, which piqued my interest in neurogenic hypertension. Consequently, I chose the laboratory of Dr. Colin Sumners at the University of Florida to conduct my postdoctoral training. Dr. Sumners is a leading expert in the field of neurogenic hypertension and his laboratory is part of the Hypertension Center at UF, which is comprised of core facilities and nearly 50 faculty members dedicated to studying high blood pressure. This training environment contributed to my successful post-doctoral NRSA proposal that afforded competence with the assessment of cardiovascular function in rodents, and perhaps more importantly, found that experimentally-induced hypertension elicited changes within the electrophysiological properties of neurons controlling blood pressure that ultimately increased their excitation. Taking these results into account, I determined that effective therapeutics should decrease or reverse this increased excitation; however, I also determined that additional training in conceptual and technical approaches aimed at understanding the electrophysiological properties of neurons was imperative to developing this line of research. Accordingly, the primary objectives of the K99-phase are to answer some fundamental questions regarding the structure and function of specific AT2R that are positioned to decrease sympathetic outflow and blood pressure, while providing additional training for in vitro patch-clamp electrophysiology. It is anticipated that determining the therapeutic utility of AT2R for neurogenic hypertension and expertise in subcellular neural electrophysiology can be complemented by professional development activities to launch my independent research career. In the first Aim, experiments will combine genetic and neuroanatomical techniques to test the specific hypothesis that AT2R-expressing neurons that make contacts onto preautonomic neurons within the paraventricular nucleus of the hypothalamus express the inhibitory neurotransmitter (GABA), thereby positioning them to decrease blood pressure and autonomic function.
In Aim 2, experiments will use patch- clamp electrophysiological techniques to test the specific hypothesis that activation of AT2R on GABA neurons that project to the PVN will facilitate inhibitory (i.e., GABAergic) neurotransmission and that this will lead to reduced activity of PVN preautonomic neurons. These experiments will not only determine precisely how activation of AT2R impact activity within a neuronal network, but they will also serve as a training vehicle for me to learn patch-clamp electrophysiology, a technique that is essential to understanding how subcellular changes in a discrete population of neurons can impact whole animal physiology. Importantly, my background, combined with expertise in electrophysiology will make my research program unique, as it will allow for the study of precisely how angiotensin-II acting through AT2R influences the excitability of specific neurons that control cardiovascular function.
Aim 3 will be contained within the R00-phase and will partner my past training with my newly-acquired skills to determine the role of AT2R in blood pressure regulation basally and during neurogenic hypertension. Using the Cre/lox system and pharmacological approaches, I will selectively activate or inhibit AT2R on neurons that project to the PVN and test the specific hypothesis that these AT2R negatively regulate blood pressure and sympathetic nervous system outflow. Collectively, the proposed studies are significant because they may uncover a novel therapeutic target for treatment of neurogenic hypertension while preparing me to establish an independent research program that addresses a problem with high
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