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Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

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The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system controls secretion of the multipotent glucocorticoid hormones. These hormones produce a dynamic regulatory influence on physiological systems in response to circadian and stress demands. Activity of the HPA axis is tightly regulated by glucocorticoid negative feedback. The focus of my research program is to determine the molecular, cellular and systems level mechanisms of glucocorticoid negative feedback present within the context of psychological stress. These glucocorticoid negative feedback actions vary across anatomical and temporal dimensions and their study requires a comprehensive multicomponent approach. I propose two career development activities over the next three years designed to maximize my pursuit of this research objective: 1] To acquire the expertise to implement within my laboratory the use of hypothalamic organotypic cultures for study of the direct glucocorticoid effects on CRH neuron function. This capability will extend the range of molecular and cell biology techniques that I can apply to mechanistic studies of glucocorticoid regulation of stimulus-secretion and stimulus-gene induction coupling, and will thereby complement my in vivo studies of HPA axis regulation, and 2] To acquire the expertise to implement within my laboratory the use of viral vector gene transfer technology. I will begin by exploring use of lentivirus to produce a localized suppression of targeted gene expression within hypothalamic organotypic cultures, and then apply effective vectors to select regions of rat brain. This technique may powerfully assist in determining whether specific molecules and cells in vitro and in vivo are necessary for glucocorticoid negative feedback effects. Acquiring new scientific methodological expertise will be made possible by visitation and consultation with Dr. Greti Aguilera (training in use of organotypic cultures), Dr. Yosef Refaelli (training in generation and validation of lentivirus expressing short hairpin RNAs) and Dr. Robert Sapolsky (training in viral vector microinfusion in target rat brain regions and validation of in vivo efficacy). A comprehensive understanding of glucocorticoid negative feedback mechanisms is essential to determining the clinical basis of HPA axis dysregulation and its ramifications. Uncontrolled psychological stress and associated abnormal HPA axis activity are contributing factors to a number of pathophysiological conditions prevalent in our society, such as hypertension, atherosclerosis, insulin resistance, asthma, altered immunity and psychiatric mood disorders. The proposed activities of this application will substantially advance my career development and maximize my research contributions to the understanding of HPA axis regulation. PUBLIC HEALTH RELEVANCE Increased secretion of the stress hormone, cortisol, has been implicated as a major biological factor that contributes to the adverse physical and psychological consequences of chronic stress. This project will identify new mechanisms by which cortisol secretion is controlled.

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