Mechanisms of BDNF and Glucocorticoid Action

BDNF 和糖皮质激素作用的机制

基本信息

批准号：
7928970
负责人：
MOSES VICTOR CHAO
金额：
$ 51.67万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928970
关键词：
Adrenal Cortex Adrenal Glands Affect Antibodies Anxiety Applications Grants Behavior Biological Brain Brain-Derived Neurotrophic Factor Bypass Candidate Disease Gene Cell Proliferation Regulation Cell Survival Cells Cessation of life Cognition Cognitive Communication Event Feedback Gene Expression Regulation Gene Targeting Genetic Transcription Glucocorticoid Receptor Glucocorticoids Hippocampus (Brain)Hydrocortisone Laboratories Lead Learning Maps Measures Mediating Memory Mental Depression Metabolic Molecular Mus N-terminal Nervous system structure Neuraxis Neurons Neurosecretory Systems Pattern Phosphorylation Phosphorylation Site Phosphotransferases Physiological Pituitary Gland Pituitary-Adrenal System Protein Kinase Proteins Proteomics Rattus Receptor Gene Receptor Protein-Tyrosine Kinases Recovery Regulation Role Serine Signal Pathway Signal Transduction Site Stress Synaptic plasticity Testing Transcriptional Regulation base biological adaptation to stress brain tissue in vivo insight mutant neurotrophic factor numb protein public health relevance receptor receptor function research study response

项目摘要

DESCRIPTION (provided by applicant): Glucocorticoids produced by the adrenal cortex exert many effects in the central nervous system ranging from spatial learning and cognition to stress and depression. Although high levels of glucocorticoids can be detrimental, in moderate concentrations, they can facilitate synaptic plasticity in the hippocampus and neuronal cell survival. The neuroprotective, anti-anxiety, and metabolic effects of glucocorticoids are carried out by the glucocorticoid receptor, which is abundantly expressed in the brain. Interestingly, the effects of glucocorticoids upon neuronal circuits are also strongly influenced by neurotrophins, such as Brain Derived Neurotrophic Factor (BDNF). However, the molecular mechanism of this regulation has not been explored. Recent evidence from our laboratories indicates there is bi-directional signaling between glucocorticoids and neurotrophins. For example, while BDNF signals through a Trk receptor tyrosine kinase, glucocorticoid receptor can bypass the need for BDNF and activate Trk signaling in neuronal cells (Jeanneteau et al PNAS 2008). In a reciprocal interaction, we have recently found that BDNF treatment promotes the phosphorylation of glucocorticoid receptor in neurons at several newly discovered sites. This proposal will dissect the biological consequences of BDNF-dependent phosphorylation of glucocorticoid receptor. Our hypothesis is that by altering phosphorylation, BDNF modulates glucocorticoid receptor gene regulatory functions, which in turn affects hippocampal-pituitary-adrenal (HPA) axis activity. These studies will begin to define the molecular mechanisms that affect feedback control and activity of the HPA system, and provide insight into how glucocorticoids and BDNF influence adaptive and maladaptive actions that are relevant to memory formation, stress response and depression. PUBLIC HEALTH RELEVANCE: Understanding communication between neurotrophins and glucocorticoids will provide insights into the mechanisms that mediate depression, cognitive abilities and stress.

描述（由申请人提供）：肾上腺皮质产生的糖皮质激素对中枢神经系统产生许多影响，从空间学习和认知到压力和抑郁。尽管高水平的糖皮质激素可能有害，但中等浓度，它们可以促进海马和神经元细胞存活中的突触可塑性。糖皮质激素的神经保护性，抗焦虑和代谢作用是由糖皮质激素受体执行的，糖皮质激素受体在大脑中大量表达。有趣的是，糖皮质激素对神经元回路的影响也受到神经营养蛋白的强烈影响，例如脑衍生的神经营养因子（BDNF）。但是，尚未探索该调节的分子机制。我们实验室的最新证据表明，糖皮质激素和神经营养蛋白之间存在双向信号传导。例如，尽管BDNF信号通过TRK受体酪氨酸激酶，但糖皮质激素受体可以绕过对BDNF的需求，并激活神经元细胞中的TRK信号传导（Jeanneteau等人PNAS 2008）。在相互的相互作用中，我们最近发现BDNF处理促进了几个新发现的位点神经元中糖皮质激素受体的磷酸化。该建议将剖析糖皮质激素受体的BDNF依赖性磷酸化的生物学后果。我们的假设是，通过改变磷酸化，BDNF调节了糖皮质激素受体基因调节功能，从而影响海马 - 垂体 - 肾上腺肾上腺（HPA）轴活动。这些研究将开始定义影响HPA系统反馈控制和活性的分子机制，并洞悉糖皮质激素和BDNF如何影响与记忆形成，压力反应和抑郁症相关的适应性和适应不良的作用。公共卫生相关性：了解神经营养蛋白和糖皮质激素之间的交流将提供有关介导抑郁症，认知能力和压力的机制的见解。