The Experimental Neurogenic Hypertension Program is a long-standing multidisciplinary research program focusing on the reciprocal interaction between the brain and the circulatory system. The central theme of the program is that, while the brain exerts a powerful influence over the circulation, the circulatory system, in turn, can have profound effects on the brain. Alterations of this delicate balance can produce hypertension and disrupt brain function. The present renewal application is organized in three Projects supported by three Cores. The Projects address diverse aspects of the central theme, but share a common focus on angiotensin II and its recently-recognized signaling system NAD(P)H oxidase. Project 1 investigates the mechanisms by which angiotensin II-induced hypertension impairs critical homeostatic mechanisms that provide blood flow to active brain regions, and examines on the role of NAD(P)H oxidase in the cerebrovascular dysfunction. Project 2 focuses on angiotensin receptors in the nucleus of the solitary tract, their relationships to catecholaminergic receptors and NAD(P)H oxidase subunits, and the changes in their subcellular targeting brought about by chronic intermittent hypoxia or angiotensin II-induced hypertension. Project 3 examines the cellular mechanisms underlying the effects of estrogens, androgens and progestins on neurons in the rostroventrolateral medulla, focusing on angiotensin receptors, and NAD(P)H oxidase subunits. The Projects are supported by an Administrative Core, a Molecular Biology-Mouse Core and a Neuroanatomy-Imaging Core. All Projects combine neuroanatomical, neurophysiological and molecular approaches to test the proposed hypothesis. The Projects build on each other's strengths so that the scientific output of one Project interacts synergistically with the research proposed in other Projects. Thus, the collective scientific outcome of the Program is anticipated to be greater than the sum of its individual components. The proposed studies are relevant to human diseases, such as hypertension-induced cognitive dysfunction, cardiovascular complications of sleep apnea, and cardiovascular diseases in post-menopausal women.
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