Role of the CNS in Inappropriate Vasopressin Release Associated with Cirrhosis

描述（由申请人提供）：申请人计划在大学医学中心担任内科科学家。本培训计划包括应用最先进的研究技术来研究肝脏疾病动物模型中低钠血症的病理生理学。低钠血症是临床上最常见的电解质紊乱。问题：肝硬化是一种慢性进行性疾病，与腹水和低钠血症相关。抗利尿激素，抗利尿激素的循环水平增加，有助于腹水和低钠血症的发展。虽然一段时间以来人们已经知道中枢介导的抗利尿激素释放有助于肝硬化的病理生理，但其途径和机制尚未确定。目的：这些研究的目的是通过大鼠梗阻性肝硬化（胆管结扎或BDL）模型确定肝硬化期间抗利尿激素释放增加的中枢神经系统机制。具体目的：1：研究肾素-血管紧张素系统在胆管结扎大鼠血管紧张素神经元慢性活化中的作用。2：验证？表达增加的假设FosB产生细胞适应性，有助于增强抗利尿激素释放神经元的兴奋性。方法：研究将采用免疫细胞化学结合逆行轨迹追踪和免疫荧光，代谢笼研究来测量尿液和钠排泄，用无线电遥测法记录慢性血压和心率，腺相关病毒介导的敲除研究，膜片钳脑切片电生理，以及脑穿孔样本的western blot和RT-PCR分析来验证这些假设。

DESCRIPTION (provided by applicant): The applicant plans a career as a physician-scientist in a University Medical Center. This training program involves applying state of the art research techniques to study the pathophysiology of hyponatremia in an animal model of liver disease. Hyponatremia is the most frequently occurring clinical electrolyte disorder. Problem: Hepatic cirrhosis is a chronic, progressive disease that is associated with ascites and hyponatremia. Increased circulating levels of the antidiuretic hormone, vasopressin, contribute to the development of both ascites and hyponatremia. Although it has been known for some time that centrally mediated vasopressin release contributes to the pathophysiology of cirrhosis, the pathways and mechanisms responsible have not been determined. Purpose: The goal of these studies is to determine the CNS mechanisms responsible for increased vasopressin release during cirrhosis using a rat model of obstructive cirrhosis (bile duct ligation or BDL). Specific Aims: 1: Test the role of renin-angiotensin system in supporting the chronic activation of vasopressin neurons in bile duct ligated rats. 2: Test the hypothesis that increased expression of ?FosB produces cellular adaptations that contribute to increased excitability of vasopressin releasing neurons. Methods: The studies will employ immunocytochemistry in combination with retrograde track tracing and immunofluorescence, metabolism cage studies to measure urine and sodium excretion, chronic blood pressure and heart rate recording with radio telemetry, adeno- associated viral mediated knock down studies, patch clamp electrophysiology in brain slices, and western blot and RT-PCR analysis from brain punch samples to test these hypotheses.