Neural Regulation of Vasopressin Release in a Model of Dilutional Hyponatremia

稀释性低钠血症模型中加压素释放的神经调节

基本信息

批准号：
9895545
负责人：
J Thomas Cunningham
金额：
$ 56.01万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895545
关键词：
Address Affect Animal Experiments Animal Model Ascites Blood Circulation Brain Brain Stem Brain-Derived Neurotrophic Factor Cells Chlorides Chronic Cirrhosis Clinical Co-Immunoprecipitations Data Disease Electrolyte Disorder Electrophysiology (science)Equilibrium Estrogens Excretory function Female Functional disorder Heart failure Homeostasis Hormones Hyponatremia Hypothalamic structure Image Immunohistochemistry In Vitro Ligation Link Liquid substance Liver Liver Cirrhosis Liver Failure Liver diseases Measures Mediating Metabolism Methods Modality Modeling Morbidity - disease rate Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Norepinephrine Output Ovarian hormone Pathogenesis Pathway interactions Patients Peripheral Phosphorylation Physiological Plasma Premenopause Prosencephalon Rattus Regulation Reverse Transcriptase Polymerase Chain Reaction Role Sex Differences Signal Transduction Site Sodium Stimulus Synapses System Testing Urine Vasopressins Western Blotting Woman autocrine base bile duct cost designer receptors exclusively activated by designer drugs dilutional hyponatremia epidemiology study experimental study gamma-Aminobutyric Acid improved knock-down laser capture microdissection magnocellular male men mortality neuroadaptation neuroregulation new therapeutic target noradrenergic paracrine paraventricular nucleus pressure prevent protective effect receptor release factor small hairpin RNA

项目摘要

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.

目的：低钠血症是最常见的电解质紊乱，2006 年治疗费用据估计，美国每年因低钠血症造成的损失为 1.6-36 亿美元。不适当的加压素分泌是与肝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 (BDNF) 及其受体 TrkB 由大细胞表达分泌加压素进入循环的神经节细胞。我们的研究将是最先测试 BDNF-TrkB 信号在不适当的加压素释放的动物模型中的作用。我们提出，在肝功能衰竭的动物模型中，BDNF-TrkB 的刺激悬而未决系统通过改变氯离子运输来增加加压素释放，防止或逆转 Cl- 抑制。我们的假设将通过以下具体目标进行检验： 1. 确定去甲肾上腺素输入是否支持 AVP 神经元的慢性激活雄性胆管结扎大鼠的儿子。 2. 确定 BDNF 是否将 AVP 神经元激活的增加与氯离子运输失去抑制作用。 3. 测试雌激素对雌性BDL大鼠阻止AVP释放的作用。方法：该研究将采用蛋白质印迹法和免疫共沉淀法，并结合免疫组织化学和激光捕获显微切割 RT-PCR、代谢笼研究测量尿液和钠排泄、DREADD、shRNA 位点特异性敲除以及体外电生理学来检验这些假设。好处：这些实验将解决我们理解中现有的差距神经垂体功能和低钠血症的发病机制。这些研究结果实验可能会改变研究不适当的加压素释放的方式临床上概念化。