The potential to reliably and safety transfer genetic material into the central nervous system holds promise in providing gene therapy to treat both genetically-associated neuropathologies and pathologies where there is altered activity in identified neural systems that can be manipulated by modulation of genetic expression. To reach this goal, experimental strategies to optimize the delivery of genetic material must be studied in defined neuronal systems and in systems where functional actions are known and can be assessed. The vasopressin synthesizing magnocellular neurons of the hypothalamic- neurohypophyseal tract have served as an extremely valuable model for the discovery of basic principles in neurobiology. In addition, these cells play critical physiological roles in the maintenance of body fluid balance and in cardiovascular regulation. The focus of this proposal is to take advantage of our experience studying vasopressin neurons of the hypothalamic-neurohypophyseal tract. We will apply our knowledge of the basic neurobiology of this defined system to study and develop strategies for enhancing gene transfer into identified neurons, and then to test these optimized methods in pathological models where vasopressin has been implicated. Specifically, the studies in this proposal are directed at 1) devising methods to obtain maximum and specific gene transfer to the magnocellular neurons of the hypothalamic-neurohypophyseal tract, 2) inducing in magnocellular neurons the capacity to synthesize and secrete vasopressin in a genetic animal model of familial diabetes insipidus, the di/di Brattleboro rat, and 3) down-regulating the release of vasopressin in a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR).
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