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

• 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
• 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

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， 据估计，美国每年的低钠血症费用为16 - 36亿美元。加压素不当 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在巨细胞核表达 分泌加压素进入循环的神经分泌细胞。我们的研究将是第一批 测试BDNF-TrkB信号传导在不适当的加压素释放的动物模型中的作用。 我们提出，在肝衰竭动物模型中，BDNF-TrkB的活性依赖性刺激 系统通过改变氯离子转运，阻止或逆转氯离子转运， 抑制作用 我们的假设将通过以下具体目标进行检验： 1.为了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SON。 2.为了确定BDNF是否将AVP神经元的激活增加与 氯离子转运抑制丧失。 3.探讨雌激素对雌性BDL大鼠AVP释放的抑制作用。 方法：采用免疫印迹和免疫共沉淀技术， 免疫组织化学和激光捕获显微切割RT-PCR，代谢笼研究， 测量尿和钠排泄、DREADD、shRNA位点特异性敲除，以及体外 电生理学来验证这些假设。 好处：这些实验将解决我们对人类基因组学的理解中存在的一个空白。 神经垂体功能和低钠血症的发病机制。之结果 实验可能潜在地改变不适当的加压素释放的研究方式， 临床概念化。