Molecular Mechanisms of the Stress Response

应激反应的分子机制

• 批准号: 9020825
• 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/9020825
• 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; Energy Transfer; Event; Feedback; GTP-Binding Proteins; Gene Expression; Genetic Transcription; Genomics; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Health behavior; Hippocampus (Brain); Hour; Hydrocortisone; Hypothalamic structure; Knockout Mice; Knowledge; Lead; Ligands; Light; LoxP-flanked allele; 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; base; biological adaptation to stress; detector; in vivo; memory retrieval; nervous system disorder; neuropsychiatric disorder; non-genomic; novel; phosphoric diester hydrolase; prevent; receptor; response; second messenger; steroid hormone; stressor; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): 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 ¿22-adrenergic receptor (¿22AR) 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 ¿22AR, and that many of the acute effects of glucocorticoids depend on this interaction and the downstream signaling activated by ¿22AR. Here we propose to identify additional systems in which this interaction is relevant to the stress response, characterize the interaction betwee cort and ¿22AR 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.

描述（由申请人提供）：压力是引发或加剧许多神经精神疾病的重要因素。 该提案的目标是更好地了解压力影响中枢神经系统生理和行为的分子机制。 这些知识最终将导致采取更有效的措施来防止压力对行为和健康的有害影响。 压力的一个重要调节者是包括糖皮质激素信号传导的神经内分泌系统。 经典的糖皮质激素信号通过类固醇激素（糖皮质激素和盐皮质激素）受体转录因子调节基因表达。 这种基因组机制是造成数小时至数天内观察到的应激效应的部分原因。 几分钟或更长时间发生的急性应激反应也可以由糖皮质激素介导。 人们认为压力的这些影响是通过非基因组机制发生的，然而，这些机制的身份仍然很大程度上未知。 在最近的一项研究中，研究了压力对海马依赖性记忆提取的急性影响，我们发现 22-肾上腺素受体（22AR）是压力和糖皮质激素损害作用的关键介质。 基于这些和其他观察结果，我们现在假设糖皮质激素受体 (GR) 或其配体 (cort) 与 ¿22AR 之间存在特定的相互作用，并且糖皮质激素的许多急性作用取决于这种相互作用和由 ¿22AR 激活的下游信号传导。 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，在分子水平上表征 cort 和 ¿22AR 之间的相互作用，并定义介导这种一致信号传导的下游信号传导事件。 这些目标的结果将确定糖皮质激素非基因组效应的具体分子机制以及压力的急性影响，这些影响可以 在慢性压力的情况下持续存在。 由于压力会损害正常的中枢神经系统生理和行为，并加剧许多神经和精神疾病，因此了解压力影响的机制可能有助于预防。