Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

糖皮质激素负反馈：内在和外在机制

基本信息

批准号：
7263898
负责人：
ROBERT L SPENCER
金额：
$ 27.96万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
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/7263898
关键词：
Acute Adrenal Glands Adverse effects Agonist Anterior Pituitary Gland Asthma Atherosclerosis Autoimmune Diseases Brain Brain region Cardiovascular Diseases Chronic Clinical Condition Corticosterone Corticotropin Diabetes Mellitus Diagnostic Disease Dorsal ERG gene 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 Numbers Osteoporosis Pathology Pattern Personal Satisfaction Phase Physiological Pituitary Gland Post-Traumatic Stress Disorders Prefrontal Cortex Process Protein Biosynthesis Psychological Stress Range 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

项目摘要

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普遍存在的许多病理生理状况的促成因素，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。心理压力和一些心理障碍之间存在着特别动态的相互作用，尤其是抑郁症和创伤后障碍（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会导致一些正在进行的病理。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。全面了解糖皮质激素负反馈机制对于确定 HPA 轴失调及其后果的临床基础至关重要。我们提出的研究将增进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。通过监测系统多个水平（垂体、下丘脑和整个大脑）压力诱导的基因表达以及压力诱导的激素分泌，我们可以区分内在（垂体和下丘脑）和外在（整个大脑）糖皮质激素负反馈作用。我们的初步研究表明，压力引起的糖皮质激素增加会引发负反馈过程，该过程暂时可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应激诱导基因表达模式相关。通过全面检查内在和外在作用位点和时间模式的贡献，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 轴对心理压力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] 表征应激引起的糖皮质激素增加对即时和后续 HPA 轴的影响对急性心理压力的反应。