Molecular Mechanisms of the Stress Response

描述(由申请人提供)：压力是诱发或加重许多神经精神障碍的重要因素。这项建议的目的是为了更好地了解应激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预防压力对行为和健康的有害影响。压力的一个重要中介是神经内分泌系统，其中包括糖皮质激素信号。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。这种基因组机制是从几个小时到几天观察到的压力效应的部分原因。在几分钟或更长时间内发生的急性应激效应也可以通过糖皮质激素来调节。这些应激效应被认为是通过非基因组机制发生的，然而，这些机制的身份在很大程度上仍然不清楚。在最近一项关于应激对海马区依赖记忆恢复的急性影响的研究中，我们发现22-肾上腺素能受体(？22AR)是应激和糖皮质激素损害效应的关键介质。基于这些和其他观察，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，糖皮质激素的许多急性作用依赖于这种相互作用和由22AR激活的下游信号。在这里，我们建议确定这种相互作用与胁迫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的下游信号事件。这些目标的结果将确定糖皮质激素的非基因组效应和应激的急性效应的特定分子机制， 在长期压力下坚持下去。由于应激可以损害正常的中枢神经系统的生理和行为，还会加剧许多神经和精神障碍，了解应激效应背后的机制可能有助于预防它们。

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.