Neural Regulation of Vasopressin Release in a Model of Dilutional Hyponatremia

目的：低钠血症是最常见的电解质紊乱，2006年治疗费用较高。 据估计，美国每年的低钠血症约为16-36亿美元。不适当的加压素 分泌物是与肝脏和心力衰竭相关的稀释性低钠血症的主要原因。 脑源性神经营养因子及其受体TrkB在巨细胞中的表达 分泌加压素进入循环的神经安全细胞。我们的研究将是第一批 测试BDNF-TrkB信号在不适当释放加压素的动物模型中的作用。 我们认为，在肝衰竭活动的动物模型中，BDNF-TrkB的刺激是有效的 系统通过改变氯的转运来增加加压素的释放，防止或逆转氯- 抑制力。 我们的假设将通过以下具体目标进行检验： 1.确定去甲肾上腺素的输入是否支持AVP神经元的慢性激活。 雄性胆管结扎大鼠子代。 2.为了确定BDNF是否将AVP神经元的激活增加与脑内AVP神经元的变化联系起来 氯离子转运失去抑制作用。 3.检测雌激素对雌性BDL大鼠AVP释放的抑制作用。 方法：研究将采用免疫印迹和免疫共沉淀相结合的方法 免疫组织化学和激光捕获显微切割RT-PCR，代谢笼式研究 测定尿钠排泄、DREADD、shRNA位点特异性敲除，以及体外 电生理学来验证这些假说。 好处：这些实验将解决我们对 神经植物功能与低钠血症的发病机制。这些研究的结果 实验可能会改变不适当的加压素释放的研究方式，并 在临床上概念化。

Purpose: Hyponatremia is the most common electrolyte disorder and in 2006 the cost of treating hyponatremia in the US was estimated to be $1.6-$3.6 billion per year. Inappropriate vasopressin secretion is the major cause of dilutional hyponatremia associated with liver and heart failure. Brain derived neurotrophic factor (BDNF) and its receptor TrkB are expressed by magnocellular neurosectory cells that secrete vasopressin into circulation. Our studies will be among the first to test the role of the BDNF-TrkB signaling in an animal model of inappropriate vasopressin release. We propose that in an animal model of liver failure activity pendent stimulation of the BDNF-TrkB system increases vasopressin release by changing chloride transport preventing or reversing Cl- inhibition. Our hypotheses will be tested with the following Specific Aims: 1. To determine if norepinephrine inputs support chronic activation of AVP neurons in the SON of male bile duct ligated rats. 2. To determine if BDNF links the increased activation of AVP neurons to the changes in chloride transport loss of inhibition. 3. To test the role of estrogen in preventing AVP release in female BDL rats. Methods: The studies will employ Western blot and co-immunoprecipitation in combination with immunohistochemistry and laser capture microdissection RT-PCR, metabolism cage studies to measure urine and sodium excretion, DREADD, shRNA site-specific knockdown, and in vitro electrophysiology to test these hypotheses. Benefit: These experiments will address an existing gap in our understanding of neurophypophyseal function and the pathogenesis of hyponatremia. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.