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

• 批准号: 7675635
• 负责人: Joseph D. Walch
• 金额: $ 2.74万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/7675635
• 关键词: Abbreviations; Academic Medical Centers; Affect; Angiotensin II; Angiotensin Receptor; Angiotensins; Animal Model; Anterior; Arts; 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; Gene Proteins; Glutamates; Goals; 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; Son; Specific qualifier value; 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; public health relevance; receptor; relating to nervous system; research study; response; supraoptic nucleus; transcription factor

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.

申请人描述(由申请人提供)：申请人计划在大学医学中心从事内科科学家的职业生涯。这项培训计划包括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：肝硬变是一种慢性进行性疾病，与腹水和低钠血症有关。循环中抗利尿激素--加压素水平的升高会导致腹水和低钠血症的发生。虽然已经知道中枢介导的加压素释放在肝硬变的病理生理学中起作用已有一段时间了，但相关的途径和机制尚未确定。目的：这些研究的目的是利用梗阻性肝硬变(胆管结扎或BDL)的大鼠模型，确定导致肝硬变期间加压素释放增加的中枢神经系统机制。具体目的：1.检测肾素-血管紧张素系统在胆管结扎大鼠加压素神经元慢性激活中的作用。2：验证这样一种假设，即？FosB的表达增加会产生细胞适应，从而有助于增强加压素释放神经元的兴奋性。方法：采用免疫细胞化学结合逆行追踪和免疫荧光、代谢笼法测定尿钠排泄、无线电遥测慢性血压和心率、腺相关病毒介导的击倒研究、脑片膜片钳电生理、Western印迹和逆转录-聚合酶链式反应分析等方法对上述假说进行验证。公共卫生相关性：这些研究的结果将确定慢性疾病状态下液体滞留的病理生理学机制，据报道，慢性疾病状态是美国第五大主要死亡原因。