TARGETED MODULATION OF VASOPRESSIN IN BRAIN MAGNOCELLULAR NEURONS BY GENE THERAPY

可靠和安全地将遗传物质转移到 中枢神经系统有望提供基因治疗来治疗 遗传相关的神经病理学和病理学， 是可以被操纵的已识别神经系统中的活动改变 通过调节基因表达。为了实现这一目标，实验 必须研究优化遗传物质传递的战略， 定义的神经元系统和功能动作已知的系统中 可以评估。 下丘脑垂体后叶加压素合成大细胞神经元 神经垂体束是一个非常有价值的模型， 发现神经生物学的基本原理。此外，这些细胞 在维持体液平衡方面起着重要的生理作用 和心血管调节。 这项建议的重点是利用我们的经验研究 下丘脑-神经垂体束的加压素神经元。我们将 应用我们对这个定义系统的基本神经生物学知识， 研究和制定战略，加强基因转移到已确定的 神经元，然后在病理模型中测试这些优化的方法 与加压素有关 具体而言，本建议中的研究旨在1）设计 获得最大和特异性基因转移到大细胞的方法 下丘脑-神经垂体束的神经元，2）诱导 大细胞神经元合成和分泌加压素的能力 在家族性尿崩症的遗传动物模型中，DI/DI Brattleboro大鼠，3）下调后叶加压素的释放， 原发性高血压的遗传模型， 大鼠（SHR）。

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).