Mechanisms of BDNF and Glucocorticoid Action

BDNF 和糖皮质激素作用的机制

• 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
• 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

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（申请人提供）：肾上腺皮质产生的糖皮质激素在中枢神经系统中发挥多种作用，从空间学习和认知到压力和抑郁。虽然高水平的糖皮质激素可能是有害的，但在中等浓度下，它们可以促进海马突触的可塑性和神经元细胞的存活。糖皮质激素的神经保护、抗焦虑和代谢作用是通过在大脑中大量表达的糖皮质激素受体来实现的。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因子（如脑源性神经营养因子（BDNF））的强烈影响。然而，这种调控的分子机制尚未被探索。我们实验室最近的证据表明，糖皮质激素和神经营养因子之间存在双向信号传导。例如，当BDNF通过Trk受体酪氨酸激酶发出信号时，糖皮质激素受体可以绕过对BDNF的需求，激活神经元细胞中的Trk信号（Jeanneteau et al PNAS 2008）。在相互作用中，我们最近发现BDNF治疗促进了神经元中糖皮质激素受体在几个新发现的位点的磷酸化。本提案将剖析bdnf依赖性糖皮质激素受体磷酸化的生物学后果。我们的假设是，通过改变磷酸化，BDNF调节糖皮质激素受体基因调节功能，从而影响海马-垂体-肾上腺（HPA）轴的活性。这些研究将开始定义影响HPA系统反馈控制和活动的分子机制，并深入了解糖皮质激素和BDNF如何影响与记忆形成、应激反应和抑郁相关的适应和不适应行为。公共卫生相关性：了解神经营养因子和糖皮质激素之间的交流将提供对调节抑郁、认知能力和压力的机制的见解。