Role of the CNS in Inappropriate Vasopressin Release Associated with Cirrhosis

中枢神经系统在肝硬化相关加压素释放不当中的作用

基本信息

批准号：
8034764
负责人：
Joseph D. Walch
金额：
$ 2.8万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8034764
关键词：
Abbreviations Academic Medical Centers Affect Angiotensin II Angiotensin Receptor Angiotensins Animal Model Anterior Ascites Blood Circulation Blood Pressure Blood Pressure Monitors Brain Brain region Cause of Death Cells Chronic Chronic Disease Cirrhosis Clinical Congestive Heart Failure Dependovirus Development Disease Dominant-Negative Mutation Electrolyte Disorder Electrophysiology (science)Enzyme Inhibition Excretory function Family Functional disorder Gene Expression Glutamates Goals Health Heart Rate Hepatic Housing Hyponatremia Hypothalamic structure Immunofluorescence Immunologic Immunohistochemistry In Vitro Injection of therapeutic agent Ion Channel Label Laboratories Lamina Terminalis Lead Left Ligation Liquid substance Liver Cirrhosis Liver diseases Measures Mediating Medical center Metabolism Methods Modality Modeling Morbidity - disease rate Names Neural Pathways Neuraxis Neurons Neurophysiology - biologic function Neurosciences Neurotransmitters Organ Output Pathway interactions Peptidyl-Dipeptidase A Perfusion Peripheral Phenotype Physicians Plasma Posterior Pituitary Gland Progressive Disease Proteins Radio Rattus Receptor, Angiotensin, Type 1 Regulation Regulator Genes Renin-Angiotensin System Reporting Research Technics Reverse Transcriptase Polymerase Chain Reaction Role Sampling Scientist Site Slice Sodium Subfornical Organ Synapses Synaptic plasticity System Techniques Telemetry Testing Time Training Programs Transcription Factor AP-1 Up-Regulation Urine Vanilloid Vasopressin Antagonist Vasopressins Viral Water Water consumption Western Blotting adeno-associated viral vector bile duct career dilutional hyponatremia feeding immunocytochemistry improved innovation knock-down member mortality neuroadaptation organum vasculosum of the lamina terminalis paraventricular nucleus patch clamp protein expression receptor relating to nervous system research study response supraoptic nucleus transcription factor

项目摘要

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. PUBLIC HEALTH RELEVANCE: The results from these studies will determine the mechanisms that contribute to the pathophysiology of fluid retention in a chronic disease state that is reported to be the 5th leading cause of death in the USA.

描述（由申请人提供）：申请人计划在大学医学中心担任医师科学家。该培训计划涉及应用最先进的研究技术来研究肝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，与腹水和低钠血症有关。抗利尿激素、加压素的循环水平升高会导致腹水和低钠血症的发生。尽管人们早已知道中枢介导的加压素释放有助于肝硬化的病理生理学，但其相关途径和机制尚未确定。目的：这些研究的目的是利用阻塞性肝硬化大鼠模型（胆管结扎或 BDL）确定导致肝硬化期间加压素释放增加的中枢神经系统机制。具体目标： 1：测试肾素-血管紧张素系统在支持胆管结扎大鼠中加压素神经元慢性激活中的作用。图 2：检验以下假设：?FosB 表达的增加会产生细胞适应，从而有助于增加加压素释放神经元的兴奋性。方法：这些研究将采用免疫细胞化学结合逆行追踪和免疫荧光、代谢笼研究来测量尿液和钠排泄、通过无线电遥测记录慢性血压和心率、腺相关病毒介导的敲低研究、膜片钳电生理学脑切片、脑穿孔样本的蛋白质印迹和 RT-PCR 分析来检验这些假设。公共健康相关性：这些研究的结果将确定慢性疾病状态下液体潴留的病理生理学机制，据报道，慢性疾病是美国第五大死亡原因。