Molecular Mechanisms of the Stress Response

应激反应的分子机制

• 批准号: 8630024
• 负责人: STEVEN A THOMAS
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630024
• 关键词: Acute; Adrenal Cortex; Adrenal Glands; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Behavior; Binding; Binding Sites; Blood Circulation; Brain; Brain region; Cell membrane; Cells; Chinese Hamster Ovary Cell; Chronic stress; Co-Immunoprecipitations; Cognition; Cognitive; Corticosterone; Coupling; Cyclic AMP; Disease; Energy Transfer; Event; Feedback; GTP-Binding Proteins; Gene Expression; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Health behavior; Hippocampus (Brain); Hour; Hydrocortisone; Hypothalamic structure; Knowledge; Lead; Ligands; Light; Measures; Mediating; Mediator of activation protein; Membrane Proteins; Memory; Mental disorders; Mineralocorticoid Receptor; Molecular; Mus; Mutagenesis; Nature; Neurologic; Neurosecretory Systems; Peripheral; Phospholipase C; Physiological; Physiology; Pituitary Gland; Post-Traumatic Stress Disorders; Prevention; Primates; Process; Psychiatric therapeutic procedure; Psychological Stress; Rodent; Second Messenger Systems; Signal Transduction; Stress; System; Work; Yeasts; acute stress; adrenergic; base; biological adaptation to stress; detector; in vivo; memory retrieval; nervous system disorder; neuropsychiatry; non-genomic; novel; phosphoric diester hydrolase; prevent; public health relevance; receptor; response; second messenger; steroid hormone; stressor; transcription factor; yeast two hybrid system

SUMMARY Stress is an important factor in either eliciting or exacerbating many neuropsychiatric disorders. The goal of this proposal is to better understand the molecular mechanisms by which stress affects CNS physiology and behavior. Such knowledge will ultimately lead to more effective measures for preventing the deleterious effects of stress on behavior and health. A prominent mediator of stress is the neuroendocrine system that includes glucocorticoid signaling. Classic glucocorticoid signaling modulates gene expression via steroid hormone (glucocorticoid and mineralocorticoid) receptor transcription factors. This genomic mechanism is partly responsible for stress effects observed over hours to days. Acute stress effects occurring over minutes or longer can also be mediated by glucocorticoids. These effects of stress are thought to occur through non- genomic mechanisms~ however, the identity of these mechanisms remains largely unknown. In a recent study examining the acute effects of stress on hippocampus-dependent memory retrieval, we identified the ¿2- adrenergic receptor (¿2AR) as a critical mediator of the impairing effects of stress and glucocorticoids. Based on these and other observations, we now hypothesize that there is a specific interaction between either the glucocorticoid receptor (GR) or its ligand (cort) and ¿2AR, and that many of the acute effects of glucocorticoids depend on this interaction and the downstream signaling activated by ¿2AR. Here we propose to identify additional systems in which this interaction is relevant to the stress response, characterize the interaction between cort and ¿2AR at the molecular level, and define the downstream signaling events that mediate this coincident signaling. Results from these aims will identify specific molecular mechanisms for the non-genomic effects of glucocorticoids and the acute effects of stress that can persist under conditions of chronic stress. Because stress can impair normal CNS physiology and behavior, as well as exacerbate many neurologic and psychiatric disorders, understanding the mechanisms that underlie stress effects may aid in their prevention.

摘要 压力是诱发或加重许多神经精神障碍的重要因素。的目标是 这一建议是为了更好地了解应激影响中枢神经系统生理和功能的分子机制 行为。这些知识最终将导致采取更有效的措施来防止有害的 压力对行为和健康的影响。压力的一个重要中介是神经内分泌系统，它 包括糖皮质激素信号。经典糖皮质激素信号通过类固醇调节基因表达 激素(糖皮质激素和盐皮质激素)受体转录因子。这种基因组机制是 对从几小时到几天观察到的压力效应负有部分责任。几分钟内发生的急性应激效应 或更长的时间也可以通过糖皮质激素来调节。这些压力的影响被认为是通过非 基因组机制~然而，这些机制的一致性在很大程度上仍不清楚。在最近的一项研究中 研究应激对海马区依赖记忆提取的急性影响，我们发现？2- 肾上腺素能受体(？2AR)是应激和糖皮质激素损伤效应的重要中介。基座 根据这些和其他观察结果，我们现在假设，在 糖皮质激素受体(GR)或其配体(CORT)和？2AR，以及糖皮质激素的许多急性作用 依赖于这种相互作用和2AR激活的下游信号。在这里，我们建议确定 这种相互作用与应激反应相关的其他系统，表征了这种相互作用 在分子水平上在CORT和？2AR之间，并定义介导这一过程的下游信号事件 重合信号。这些目标的结果将确定非基因组的特定分子机制 糖皮质激素的影响和在慢性应激条件下可以持续的应激的急性影响。 因为应激可以损害正常的中枢神经系统的生理和行为，以及加剧许多神经和 精神障碍，了解压力效应背后的机制可能有助于预防它们。