Melanocortin system stress and HPA axis

黑皮质素系统压力和 HPA 轴

• 批准号: 7145061
• 负责人: Xin-Yun Lu
• 金额: $ 27.59万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145061
• 关键词: RNA interference; adrenocorticotropic hormone; amygdala; autoradiography; behavioral /social science research tag; binding sites; biological signal transduction; endocrine pharmacology; fos protein; hormone inhibitor; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; in situ hybridization; laboratory rat; melanocyte stimulating hormone; neural plasticity; neuropharmacology; neuroregulation; paraventricular nucleus; psychological stressor; radioimmunoassay; receptor expression; secretory protein; stereotaxic techniques; stress

DESCRIPTION (provided by applicant): Stress response is important for survival. However, prolonged exposure to stressors produces detrimental effects, increasing the susceptibility for anxiety disorders, depression, eating disorders and obesity. A common feature of these illnesses is the perturbation of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) plays a pivotal role in the mediation of stress responses, particularly HPA activation. Recently, anatomical and functional evidence indicates that the central melanocortin system, a critical regulator of energy balance, interacts with the stress system and modulates HPA activity through CRH. This system consists of two opposite signaling components, the endogenous agonist alpha-MSH and the endogenous antagonist AgRP. The goal of this project is to study the role of the melanocortin system in stress responsiveness, focusing on HPA activation. First, we plan to identify the regulatory effects of acute and chronic stress on alpha-MSH, AgRP and their common receptor MC4R by measuring their transcriptional and translational responses in two key structures within stress circuits (the paraventricular nucleus of the hypothalamus and amygdala) using in situ hybridization, receptor autoradiography and radioimmunoassay; Second, we will determine the impact of the melanocortin system on the HPA response to acute and chronic stress using pharmacologic and molecular means to alter activation status or the expression level of MC4R. Given that studies on this system have been primarily focused on the regulation of feeding and body weight in recent years, the proposed studies in this project will not only shed light on biological functions of melanocortin signaling in stress, but also provide new insights into the interface between stress and eating disorders/obesity.

描述（由申请人提供）：压力反应对于生存很重要。然而，长期暴露在压力源下会产生有害影响，增加焦虑症、抑郁症、饮食失调和肥胖的易感性。这些疾病的一个共同特征是下丘脑-垂体-肾上腺 (HPA) 轴的扰动。促肾上腺皮质激素释放激素 (CRH) 在应激反应的调节中发挥着关键作用，特别是 HPA 激活。最近，解剖学和功能证据表明，中枢黑皮质素系统是能量平衡的关键调节器，与压力系统相互作用，并通过 CRH 调节 HPA 活性。该系统由两个相反的信号成分组成，即内源性激动剂 α-MSH 和内源性拮抗剂 AgRP。该项目的目标是研究黑皮质素系统在应激反应中的作用，重点关注 HPA 激活。首先，我们计划通过测量应激回路内两个关键结构（下丘脑的室旁核和杏仁核）的转录和翻译反应，确定急性和慢性应激对 α-MSH、AgRP 及其共同受体 MC4R 的调节作用。原位杂交、受体放射自显影和放射免疫分析；其次，我们将使用药理学和分子手段改变 MC4R 的激活状态或表达水平，确定黑皮质素系统对 HPA 对急性和慢性应激反应的影响。鉴于近年来对该系统的研究主要集中在摄食和体重的调节上，该项目中提出的研究不仅将揭示黑皮质素信号在应激中的生物学功能，而且还为该界面提供了新的见解。压力与饮食失调/肥胖之间。