Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

糖皮质激素负反馈：内在和外在机制

• 批准号: 7860660
• 负责人: ROBERT L SPENCER
• 金额: $ 21.95万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860660
• 关键词: Acute; Adrenal Glands; Adverse effects; Agonist; Anterior Pituitary Gland; Asthma; Atherosclerosis; Autoimmune Diseases; Brain; Brain region; Cardiovascular Diseases; Chronic; Clinical; Corticosterone; Corticotropin; Diabetes Mellitus; Diagnostic; Disease; Dorsal; Event; Feedback; Gene Expression; Gene Expression Profile; Glucocorticoid Receptor; Glucocorticoids; Health; Hippocampus (Brain); Hormonal; Hormones; Hour; Human; Hydrocortisone; Hypertension; Hypothalamic structure; Immediate-Early Genes; Immunity; Insulin Resistance; Lead; Measures; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Microinjections; Mineralocorticoid Receptor; Molecular; Monitor; Nature; Neurosecretory Systems; Osteoporosis; Pathology; Pattern; Phase; Physiological; Pituitary Gland; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Protein Biosynthesis; Psychological Stress; Rattus; Regulation; Research Personnel; Site; Societies; Source; Stress; System; Systemic disease; Testing; abdominal fat; base; cell type; design; hypothalamic-pituitary-adrenal axis; improved; insight; neural circuit; programs; psychological stressor; relating to nervous system; reproductive; research study; response; restraint; restraint stress; stress related disorder

Uncontrolled psychological stress and associated abnormal cortisol hormone secretion patterns are a contributing factor to a number of pathophysiological conditions prevalent in our society, such as hypertension, atherosclerosis, insulin resistance, abdominal fat accumulation, asthma and altered immunity. There is an especially dynamic interplay between psychological stress and some psychological disorders, most notably depression and post traumatic disorder (PTSD). In both cases there is strong supporting evidence for dysregulation of Hypothalamic-Pituitary-Adrenal (HPA) axis activity, and the resulting dysregulated cortisol levels may contribute to some of the ongoing pathology. The most important factor controlling HPA axis activity is the negative feedback provided by glucocorticoids (e.g. cortisol and corticosterone). A comprehensive understanding of glucocorticoid negative feedback mechanisms is essential to determining the clinical basis of HPA axis dysregulation and its ramifications. We propose studies that will advance our understanding of the molecular, cellular and systems level aspects of glucocorticoid negative feedback. By monitoring stress-induced gene expression at multiple levels of the system (pituitary, hypothalamus and throughout brain) in parallel with stress-induced hormone secretion we can distinguish between the intrinsic (pituitary and hypothalamus) and extrinsic (throughout brain) glucocorticoid negative feedback actions. Our preliminary studies suggest that a stress-induced increase in glucocorticoids initiates negative feedback processes that temporally can be divided into three distinct phases: fast feedback (< 10 min), short-term feedback (about 1 hr) and delayed feedback (about 3 hr). Each phase is associated with different stress-induced gene expression patterns. By comprehensively examining the contribution of intrinsic and extrinsic sites of action and temporal patterns we will be able to accomplish the following Specific Aims: 1] Determine mechanisms by which phasic increases in glucocorticoids produce intrinsic negative feedback on the HPA axis functional response to psychological stress, 2] Characterize the extrinsic negative feedback influence on the HPA axis functional response to stress, 3] Characterize the impact of stress-induced increases of glucocorticoids on immediate and subsequent HPA axis responses to acute psychological stress.

不受控制的心理压力和相关的异常皮质醇激素分泌模式是我们社会中普遍存在多种病理生理状况的一个因素，例如高血压，动脉粥样硬化，胰岛素抵抗，腹部脂肪的积累，哮喘和免疫力。心理压力与某些心理障碍之间存在特别动态的相互作用，最著名的是抑郁症和创伤后疾病（PTSD）。在这两种情况下，都有强大的支持证据表明下丘脑 - 垂体 - 肾上腺（HPA）轴活动的失调，并且所得的失调皮质醇水平可能导致某些持续的病理学。控制HPA轴活动的最重要因素是糖皮质激素（例如皮质醇和皮质酮）提供的负反馈。对糖皮质激素负反馈机制的全面了解对于确定HPA轴功能障碍及其后果的临床基础至关重要。我们提出的研究将提高我们对糖皮质激素负反馈的分子，细胞和系统水平方面的理解。通过与应力诱导的激素分泌同时监测系统多个系统（垂体，下丘脑和整个大脑）处的应激诱导的基因表达，我们可以区分固有（垂体和下丘脑）和外在（整个大脑）糖皮质激素负反馈作用。我们的初步研究表明，糖皮质激素的压力诱导的增加会引发负反馈过程，这些反馈过程可以分为三个不同的阶段：快速反馈（<10分钟），短期反馈（约1小时）和延迟反馈（约3小时）。每个阶段都与不同的压力诱导的基因表达模式有关。通过全面研究固有和外在的作用和时间模式的贡献，我们将能够完成以下特定目的：1]确定糖皮质激素的阶段增加的机制，从而对HPA轴对HPA轴对心理压力的功能响应的质量响应的影响进行了反馈的影响，2]糖皮质激素对急性心理压力的直接和随后的HPA轴反应的增加。