Homeostatic Regulation of Supraoptic Neurons: Role of BDNF

视上神经元的稳态调节：BDNF 的作用

基本信息

批准号：
9242065
负责人：
J Thomas Cunningham
金额：
$ 36.5万
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：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242065
关键词：
Address Adult Affect Animal Experiments Anterior Argipressin Biological Neural Networks Blood Circulation Body Fluids Brain Brain-Derived Neurotrophic Factor Cells Chlorides Clinical Data Dehydration Disease Electrolyte Disorder Electrophysiology (science)Equilibrium Experimental Water Deprivation FDA approved Financial compensation Glutamates Goals Health Heart Heart failure Homeostasis Hyponatremia Hypothalamic structure In Vitro Investigation Knowledge Laboratories Lamina Terminalis Lasers Link Literature Liver Liver Failure Long-Term Depression Long-Term Potentiation Mediating Messenger RNA Methods Morbidity - disease rate N-Methyl-D-Aspartate Receptors N-Methylaspartate NR2B NMDA receptor Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Osmolalities Patients Pharmacologic Substance Phosphorylation Phosphotransferases Physiological Pituitary Gland Plasma Posterior Pituitary Gland Potassium Chloride Publishing Rattus Receptor Activation Regulation Research Role Signal Pathway Signal Transduction Stress Synapses System Testing Time Up-Regulation Vasopressins Water Water consumption autocrine cell water controlled release cost dilutional hyponatremia experimental study gamma-Aminobutyric Acid in vivo magnocellular member mortality neurotransmission novel paraventricular nucleus phospholipase C gamma postsynaptic programs public health relevance src-Family Kinases

项目摘要

DESCRIPTION (provided by applicant): The goal of these studies is to determine how Brain derived neurotrophic factor (BDNF) and its receptor TrkB influence vasopressin release to a progressive physiological challenge, water deprivation. Our data suggest that BDNF may facilitate both glutamate and GABA signaling during water deprivation by causing phosphorylation NR2B and increasing the expression of the chloride transporter KCC2. Increased NR2B phosphorylation would increase NMDA receptor activation enhancing vasopressin release while increased KCC2 activity could increase the inhibitory effects of GABA representing a homeostatic synaptic compensation to increased excitation during water deprivation. Specific Aim 1: to determine the role of neurohypophysial BDNF-TrkB signaling and enhanced glutamate action through NR2B phosphorylation during sustained vasopressin release induced by water deprivation. Hypothesis: Phosphorylation of TrkB associated with water deprivation leads to enhanced glutamate activity due to phosphorylation of NR2B NMDA receptor subunits through Fyn kinase, a member of the Src kinase family contributing to NMDA mediated plasticity in MNCs Specific Aim 2: to test the hypothesis that neurohypophysial BDNF-TrkB signaling enhances the inhibitory effects of GABA during water deprivation. Hypothesis: BDNF-TrkB signaling during water deprivation increases KCC2 expression enhancing the inhibitory effects of GABA in MNCs via Src kinase and without the activation of Phospholipase C gamma. Methods: These experiments will for the first time define the roles of BDNF-TrkB signaling in the homeostatic regulation of sustained AVP release. An integrative approach will be employed that includes in vitro and in vivo electrophysiological experiments, whole animal experiments in which TrkB and Src kinase antagonists will be locally applied to the SON, and functional studies of water balance and AVP release in the rat. Benefit: These experiments will address an existing gap in our understanding of the physiological regulation of neurohypophyseal function. The findings of these experiments could potentially alter the way that inappropriate vasopressin release is studied and conceptualized clinically.

描述（由申请人提供）：这些研究的目的是确定脑衍生的神经营养因子（BDNF）及其受体TRKB如何影响加压素的释放到渐进的生理挑战，水剥夺。我们的数据表明，通过引起磷酸化NR2B并增加氯化物转运蛋白KCC2的表达，BDNF可能会促进谷氨酸和GABA信号传导。 NR2B磷酸化的增加将增加NMDA受体激活增强血管加压素的释放，而KCC2活性的增加可能会增加代表稳态突触补偿的GABA的抑制作用，从而增加了在水剥夺过程中兴奋的增加。具体目标1：确定神经型物理BDNF-TRKB信号传导和通过NR2B磷酸化在持续的加压素释放期间通过水剥夺引起的持续加压素释放期间的作用。假设：与水剥夺相关的TRKB的磷酸化导致谷氨酸的活性增强，这是由于NR2B NMDA受体亚基通过FYN激酶的磷酸化而引起的，SRC激酶的成员，SRC激酶家族的成员有助于NMDA介导的MNCS特定目标2：neuryrys festry heyurhospoptial hyurhohysty hyuroshospoptial hyurhohohysty，水剥夺期间GABA的抑制作用。假设：水剥夺期间的BDNF-TRKB信号传导增加KCC2的表达，从而增强了通过SRC激酶在MNC中增强GABA的抑制作用，而没有激活磷脂酶C伽马。方法：这些实验将首次定义BDNF-TRKB信号在持续AVP释放的稳态调节中的作用。将采用一种综合方法，其中包括体外和体内电生理实验，整个动物实验，其中TRKB和SRC激酶拮抗剂将局部应用于SON，以及对大鼠水平和AVP释放的功能研究。好处：这些实验将解决我们对神经摩托学功能生理调节的理解时的现有差距。这些实验的发现可能会改变临床研究和概念化不适当的加压素释放的方式。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Editorial Focus: the brain renin-angiotensin system and hypertension. Focus on: hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent.

编辑焦点：大脑肾素-血管紧张素系统和高血压。

DOI：
10.1152/ajpregu.00272.2013
发表时间：
2013
期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
0
作者：
Cunningham,JThomas
通讯作者：
Cunningham,JThomas