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: 7626869
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626869
• 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 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; depression; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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流行的许多病理生理学状况的促成因素，例如高血压、动脉粥样硬化、胰岛素抵抗、腹部脂肪堆积、哮喘和免疫力改变。心理压力和某些心理障碍之间存在着特别动态的相互作用，最明显的是抑郁症和创伤后精神障碍（PTSD）。在这两种情况下，都有强有力的证据支持下丘脑-垂体-肾上腺（HPA）轴活动失调，由此产生的皮质醇水平失调可能导致一些正在进行的病理学。控制HPA轴活动的最重要因素是糖皮质激素（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理解对于确定HPA轴失调及其后果的临床基础至关重要。我们提出的研究，将促进我们的糖皮质激素负反馈的分子，细胞和系统水平方面的理解。通过监测应激诱导的基因表达在多个水平的系统（垂体，下丘脑和整个大脑）与应激诱导的激素分泌平行，我们可以区分内在（垂体和下丘脑）和外在（整个大脑）糖皮质激素负反馈行动。我们的初步研究表明，应激诱导的糖皮质激素增加启动负反馈过程，在时间上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）。每个阶段与不同的胁迫诱导的基因表达模式相关。通过全面检查内在和外在作用部位和时间模式的贡献，我们将能够实现以下具体目标：1]确定糖皮质激素的阶段性增加对HPA轴对心理应激的功能反应产生内在负反馈的机制，2]表征外在负反馈对HPA轴对应激的功能反应的影响，3]描述应激诱导的糖皮质激素增加对急性心理应激的立即和随后HPA轴反应的影响。