DESCRIPTION (Provided by applicant): This Program Project Grant continues to focus on Integrative Neurobiology of Cardiovascular Regulation. Now in its 40th year, it represents a major scientific emphasis of the Cardiovascular Research Center at lowa. The strength of this renewal is based on the cohesion and synergy of its senior leadership, its constant evolution in concepts and approaches with new investigators and the continuum of the effort from discovery of mechanisms to their translation into disease states in animal models and humans. The four projects represent a functional integration of central neurohormonal processes which through interdependent molecular mechanisms involving neuroplasticity, oxidation, and inflammation induce pathological states of anxiety, hypertension and vascular damage. Project I: "Sites and Mechanisms of CNS Neuroplasticity in the Sensitization of Hypertension" (Johnson, Kwitek) explores mechanisms that induce hypertension through the upregulation of signaling molecules in the key brain nuclei comprising the Angiotensin/Aldosterone sensitive components of the neural network controlling blood pressure. Project II: "Does Anxiety Cause Vascular Dysfunction Through Inflammation and Sympathetic Activation?" (Haynes, Fiedorowicz, Pierce) considers vascular dysfunction peripherally as well as centrally (cerebrally) as pathological underpinnings of an inflammatory oxidative process that increases sympathetic activity and cardiovascular risks in humans with severe anxiety. Project III: "Neurohormonal Regulation of the Innate Immune System is Proinflammatory in a Genetic Model of Hypertension" (Abboud, Ballas, Zavazava) identifies a strong regulatory influence of cholinergic and ATI receptors on the inflammatory immune pathological process in hypertension with vascular and renal damage. Project IV: "Methionine Sulfoxide Reductase A: a novel Molecular Determinant of Autonomic Regulation and Hypertensive End-Organ Damage" (Chapleau, Anderson, Weiss) explores the ability to target changes in the oxidative process to specific brain sites and vascular muscle and thereby alter the course of hypertension and vascular pathology. Novel concepts about inflammatory and oxidative processes in hypertension and vasculopathy are explored. The technical approaches and animal models are well established, and there is a thematic translational convergence of molecular mechanisms in hypertension, anxiety, dysautonomia and vascular pathology. Common threads create the intellectual fabric where the integrated outcome will be far greater than the sum of the components.

Hypertension and vascular damage are the most common causes of cardiovascular mortality, and anxiety in humans increases cardiovascular risks significantly. The four projects we propose will define molecular mechanisms that involve pathological processes of neuroplasticity, oxidation, and inflammation in animal models of hypertension and in humans suffering from anxiety. Their translational potential into therapeutic interventions in patients is very high.