Role of Estrogen Receptors and Neurohypophyseal Gene Expression in Vasopressin Release in a Model of Dilutional Hyponatremia

稀释性低钠血症模型中雌激素受体和神经垂体基因表达在加压素释放中的作用

• 批准号: 10608943
• 负责人: DIANNA HUYEN-TRAM NGUYEN
• 金额: $ 3.37万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608943
• 关键词: Acute; Animal Model; Arginine; Body Fluids; Body Water; Brain-Derived Neurotrophic Factor; Cardiovascular system; Central Nervous System; Chronic Disease; Circulation; Cirrhosis; Clinical; Congestive Heart Failure; Data; Development; ESR1 gene; Electrolyte Disorder; Estrogen Receptor beta; Estrogen Receptors; Female; Fluid Balance; Fostering; Fulvestrant; Functional disorder; GPER gene; Gene Expression; Goals; Heart failure; Hormones; Hospitals; Hyponatremia; Hypothalamic structure; Infusion procedures; Injury; Kidney; Knowledge; Ligation; Liquid substance; Literature; Liver Cirrhosis; Liver Failure; Modeling; Neurons; Osmoregulation; Outcome; Oxytocin; Pathogenesis; Patients; Peripheral; Physiological; Posterior Pituitary Hormones; Prognosis; Rattus; Regulation; Research; Resources; Risk Factors; Role; Sex Differences; Signal Transduction; Sodium; Spinal cord injury; Subarachnoid Hemorrhage; Surrogate Markers; System; Testing; Therapeutic; Trauma; United States; V2 Receptors; Vasopressins; Water; antagonist; bile duct; clinical practice; cost; defined contribution; dilutional hyponatremia; experimental study; insight; magnocellular; male; mortality; new therapeutic target; novel; novel therapeutic intervention; older patient; paraventricular nucleus; patient population; sex; sexual dimorphism; supraoptic nucleus; transcriptomics

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. Our previous studies have also shown that, in male BDL rats, BDNF-TrkB signaling in the SON contributes sustained AVP and copeptin (a clinical surrogate for AVP 1-3) release, and hyponatremia 4. However, little is known about the role of sex differences in hyponatremia5. Our data show that female BDL rats do not develop hyponatremia or increased AVP release6. Instead female BDL rats show increased release of oxytocin6 . Our findings also suggest that the effects of BDL on neurohypophyseal hormones may be sexually dimorphic. Our central hypothesis is that ER in the hypothalamo-neurohypophyseal system (HNS) contribute, at least in part, to sex differences seen in the BDL model of dilutional hyponatremia. Our hypotheses will be tested with the following Specific Aims: Aim 1 will define the contributions of estrogen receptors in hypothalamo-neurohypophyseal neurons to sex differences in a model of dilutional hyponatremia Aim 2 will determine differences in SON gene expression that may contribute to underlying sex differences in AVP release in a model of dilutional hyponatremia 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。我们的 先前的研究还表明，在雄性 BDL 大鼠中，SON 中的 BDNF-TrkB 信号传导 有助于持续释放 AVP 和和肽素（AVP 1-3 的临床替代物），并且 低钠血症 4. 然而，人们对性别差异在低钠血症中的作用知之甚少5。我们的 数据显示，雌性 BDL 大鼠不会出现低钠血症或 AVP 释放增加6。反而 雌性 BDL 大鼠的催产素 6 释放量增加。我们的研究结果还表明，影响 BDL 对神经垂体激素的影响可能是性别二态性的。我们的中心假设是 下丘脑神经垂体系统 (HNS) 中的 ER 至少部分地影响性 稀释性低钠血症的 BDL 模型中观察到的差异。 我们的假设将通过以下具体目标进行检验： 目标 1 将定义雌激素受体在下丘脑-神经垂体中的贡献 稀释性低钠血症模型中神经元对性别差异的影响 目标 2 将确定可能影响潜在性别的 SON 基因表达差异 稀释性低钠血症模型中 AVP 释放的差异 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。