Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

描述(申请人提供)：糖皮质激素对每个生理系统都有强大的多因素调节作用。糖皮质激素分泌的失调模式，通常是由于慢性压力造成的，对身心健康有不利影响。糖皮质激素分泌失调与一些心理障碍(如抑郁症和创伤后应激障碍)和其他生物医学疾病(如II型糖尿病、慢性疲劳综合征、纤维肌痛)密切相关。糖皮质激素的分泌受神经内分泌下丘脑-垂体-肾上腺(HPA)轴系统的控制，而调节HPA轴活动的主要因素是糖皮质激素的负反馈。对糖皮质激素负反馈的机制了解有限。为了解决这一认识上的差距，这项正在进行的研究项目将确定糖皮质激素负反馈的分子、细胞和系统水平的机制。这一知识对于辨别慢性应激如何导致糖皮质激素负反馈功能改变是必要的，它将为针对性干预指明新的策略，以防止甚至逆转与慢性应激相关的糖皮质激素负反馈功能的改变。该项目的指导性假设是，糖皮质激素在HPA轴的内在解剖元素内产生多种影响，并对决定HPA轴活动的神经回路产生影响。这些糖皮质激素的作用有不同的起效和表达时间框架，以及不同的潜在分子机制。通过建立这些细胞的作用部位和表达的时间模式，该项目将确定糖皮质激素负反馈的具体机制。该项目之前的工作确定了糖皮质激素在糖皮质激素阶段性增加后的不同时间间隔内明显的独立作用，可区分为快速(15分钟)、短期(~1小时)和延迟(~3小时)负反馈作用。围绕这一概念框架组织的四个具体目标将涉及以下内容：目标1]确定糖皮质激素在下丘脑室旁核产生快速负反馈的时间需求和受体机制。[目的]利用下丘脑器官培养方法，探讨糖皮质激素对CRH神经元产生内源性负反馈的细胞和分子机制。[目的]探讨糖皮质激素短期和延迟性负反馈的体内机制。[目的]探讨慢性应激适应与糖皮质激素负反馈功能的关系。从这些拟议的研究中获得的新信息可以应用于1)设计更好的(更敏感或更具启发性的)HPA轴相关措施和患者群体中的挑战条件，2)识别与HPA轴失调相关的新候选风险基因，以及3)开发新的治疗方法，可以选择性地使HPA轴功能正常化，而不会干扰全身适当的糖皮质激素信号。

DESCRIPTION (provided by applicant): Glucocorticoid hormones have powerful multifactorial regulatory effects on every physiological system. Dysregulated patterns of glucocorticoid hormone secretion, often as a result of chronic stress, have adverse effects on physical and mental health. Dysregulation of glucocorticoid secretion is strongly associated with some psychological disorders (e.g. depression and posttraumatic stress disorder) and other biomedical disorders (e.g. Type II diabetes, chronic fatigue syndrome, fibromyalgia). Glucocorticoid secretion is controlled by the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis system, and the principal factor that has regulatory control over HPA axis activity is glucocorticoid negative feedback. Understanding of the mechanisms responsible for glucocorticoid negative feedback is limited. To address that gap in knowledge, this ongoing research project will determine the molecular, cellular and systems level mechanisms of glucocorticoid negative feedback. This knowledge is necessary to discern how chronic stress leads to altered glucocorticoid negative feedback function, and it will point to new strategies for targeted interventions that will prevent and perhaps reverse alteration of glucocorticoid negative feedback function associated with chronic stress. The guiding hypothesis of this project is that glucocorticoids produce multiple effects within the intrinsic anatomical elements of the HPA axis as well as effects on neural circuits that dictate the moment-to-moment HPA axis activity. These glucocorticoid effects have distinct time frames of onset and expression, as well as separate underlying molecular mechanisms. By establishing these cellular sites of action and temporal patterns of expression this project will determine specific mechanisms of glucocorticoid negative feedback. Previous work on this project identified independent actions of glucocorticoids that are evident within different time intervals after a phasic increase in glucocorticoids that can be distinguished as fast (< 15 min), short-term (~ 1 hr), and delayed (~3 hr) negative feedback actions. Four Specific Aims organized around this conceptual framework will address the following: Aim 1] To determine the temporal requirements and receptor mechanisms by which glucocorticoids produce fast negative feedback at the hypothalamic paraventricular nucleus. Aim 2] To use hypothalamic organotypic cultures to determine cellular and molecular mechanisms by which glucocorticoids produce intrinsic negative feedback on CRH neurons. Aim 3] To determine in vivo mechanisms of glucocorticoid short-term and delayed negative feedback. Aim 4] To determine the relationship between chronic stress adaptation and glucocorticoid negative feedback function. The new information derived from these proposed studies can then be applied to 1) the design of better (more sensitive or revealing) HPA axis related measures and challenge conditions in patient populations, 2) identification of new candidate risk genes associated with HPA axis dysregulation, and 3) development of new treatments that may selectively normalize HPA axis function without disturbing appropriate glucocorticoid signaling throughout the body.