PROJECT SUMMARY Hypertension is a major risk factor for cardiovascular disease, the leading cause of mortality globally. Despite major milestones in understanding the pathophysiology of the disease, 20% of patients suffer from drug-resistant hypertension where blood pressure is uncontrollable despite the use of 3-4 medications. Patients with resistant hypertension often exhibit increased sympathetic nerve activity, suggesting the disease may have neural origins. The homeostatic baroreflex is a neural reflex capable of sensing elevations in blood pressure and reducing sympathetic nerve activity to restore blood pressure back to optimal levels. Classically, the baroreflex has not been thought to play a role in the development of hypertension and is rather thought to play a role in short-term blood pressure regulation. This is due to earlier studies that utilized animal models where nerves innervating the aortic arch and the carotid sinus were ablated, to investigate whether arterial baroreceptor ablation leads to hypertension. A major issue with these studies is the fact that the carotid sinus contains both the inhibitory arterial baroreceptors and excitatory chemoreceptors. Thus, there is a need to develop novel approaches that selectively target arterial baroreceptors. To this end, I have developed a novel approach to selectively target sensory neurons innervating the aortic arch in mice. My preliminary studies suggest that, contrary to common belief, arterial baroreceptors express more than the classical mechanosensitive ion channels. This includes transient receptor potential and epithelia sodium channels. Thus, I hypothesize that arterial baroreceptors utilize a combination of gene products to transduce the stretch exerted on the aortic arch into action potentials that trigger reflex reductions in blood pressure. I further hypothesize that chronic elevations in blood pressure disrupts the expression of these gene products to alter the relationship between vascular stretch, neuronal firing, and perfusion pressure. During the K99 phase, I will pursue two aims that require training in the appropriate cellular approaches to interrogate the first hypothesis. This will be done by utilizing single nucleotide RNA sequencing in Aim 1 to unravel the genetic identity of arterial baroreceptors. Aim 2 will link gene product expression to neuronal discharge during baroreception using in vivo multiphoton calcium imaging. During the R00 phase, I will combine the acquired cellular approaches with my existing integrative approaches to investigate the role arterial baroreceptors play in the development of renovascular hypertension. Collectively, the proposed studies will lead to novel fundamental understanding of whether the baroreflex is implicated in hypertension, which may represent a novel target for the development of anti-hypertensive therapeutics. In addition, strong mentorship by Drs. Eric Krause and Annette de Kloet, as well as a Mentoring Committee comprised of experts in the proposed techniques; will provide conceptual and methodological training, to achieve the research goals and prepare me to establish an independent research program.

PROJECT NARRATIVE Classically, the role that the homeostatic baroreflex plays in the development of cardiovascular disease has been questionable, due to the lack of tools that selectively target arterial baroreceptors. We have developed a novel approach to selectively target arterial baroreceptors that innervate the aortic arch. Our goal is to utilize this approach to revisit the role that the baroreflex plays in the development of hypertension.