Beta Endorphin Neurons and the Control of Homeostasis

β内啡肽神经元和体内平衡的控制

• 批准号: 7194361
• 负责人: Martin Jeffrey Kelly
• 金额: $ 33.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194361
• 关键词: Affect; Animals; Attenuated; Binding; Brain; Breast; Cell model; Chemicals; Cloning; Coupling; Cyclic AMP-Dependent Protein Kinases; Development; Electrophysiology (science); Endorphins; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Exhibits; Female; G-Protein-Coupled Receptors; Gene Expression; Genetic Transcription; Genomics; Goals; Histocytochemistry; Homeostasis; Hormone replacement therapy; Hot flushes; Hypothalamic structure; Lead; Light; Mediating; Membrane; Molecular; Molecular Biology; Moods; Motivation; Mus; Nature; Neuraxis; Neurons; Opioid Receptor; Osteoporosis; POMC gene; Pathway interactions; Peripheral; Phospholipase C; Phosphotransferases; Physiology; Population; Potassium Channel; Pro-Opiomelanocortin; Protein Kinase; Protein Kinase C; Publications; RNA Splicing; Range; Receptor Signaling; Regulation; Reproduction; Research; Rewards; Risk; Selective Estrogen Receptor Modulators; Signal Pathway; Signal Transduction; Synaptic Transmission; Synthesis Chemistry; System; Temperature; Testing; Transcript; Uterine Cancer; Variant; Woman; Women' s Health; Work; base; beta-Endorphin; biological adaptation to stress; cancer risk; citrate carrier; dopaminergic neuron; feeding; gamma-Aminobutyric Acid; human ESR1 protein; insight; interdisciplinary approach; mu opioid receptors; novel; prevent; receptor; tool

DESCRIPTION (provided by applicant): The long-range goal of the proposed research is to define the rapid signaling mechanism(s) by which estrogen (E2) acts in hypothalamic POMC (beta-endorphin) and dopamine neurons to modulate homeostatic functions such as reproduction, temperature regulation, stress responses, feeding, motivation and reward; and to incorporate this information into a cellular model of membrane-initiated signaling by E2. Understanding these novel, fast actions of E2 and how they relate to its genomic actions will provide insight into a fundamental problem facing approximately 50 million women in need of hormone replacement therapy. E2 is neuroprotective, prevents hot flushes, has a positive influence on mood and affect, is protective against osteoporosis but increases the risk of breast and uterine cancers. Selective estrogen receptor modulators (SERMs) that produce the beneficial effects of E2 in the central nervous system (CNS) but lack the cancer risk profile of E2 are greatly needed. It has been suggested that the nuclear estrogen receptors ER alpha and ER beta are responsible for all of the actions of E2, but our studies provide strong evidence for a novel membrane-associated E2 receptor that mediates rapid signaling in the CNS. The receptor has not yet been identified nor is the nature of its coupling to effector systems completely understood. We recently synthesized the first SERM, STX, that specifically targets the membrane receptor, which will allow us to rigorously characterize and eventually identify the membrane ER. Our hypothesis is that the rapid effects of E2 are due to its binding to a G protein-coupled receptor that activates kinase pathways to attenuate GABA-B and mu-opioid receptor activity. In this proposal, we seek to elucidate the cellular cascades activated by STX and to further characterize the receptor mediating these effects. We will use a unique range of cellular, molecular and chemical tools to characterize the Gq-coupled E2 receptor, its coupling to signaling pathways in hypothalamic neurons and its functional consequences. The specific aims are: (1) To test whether STX uses the same receptor-mediated signaling pathway as E2 to uncouple GABA-B and mu-opioid receptors from K+ channels in POMC and dopamine neurons. (2) To test whether STX alters gene expression in a sub-group of E2-regulated transcripts that are critical for synaptic transmission in hypothalamic neurons. (3) To test whether the rapid effects of E2 and S TX on POMC and dopamine neurons are present in ER alpha and beta-deficient mice, and based on the results develop a cloning strategy for the membrane ER. These studies will not only identify the pathway(s) that is critical for rapid signaling in hypothalamic neurons but also should allow the development of new SERMs specifically targeting critical brain circuits involved in the control of homeostasis in the female.

描述（由申请人提供）：拟议的研究的远程目标是定义雌激素（E2）在下丘脑POMC（β-内芬）和多巴胺神经元中作用的快速信号传导机制，以调节稳固功能，例如繁殖，温度调节，压力反应，喂养，动机和奖励；并将这些信息纳入E2引起的膜发射信号的细胞模型。了解E2的这些新颖，快速的动作及其与其基因组作用如何相关，将为您提供大约5000万需要激素替代疗法的妇女面临的基本问题。 E2具有神经保护性，可防止潮热，对情绪和情感产生积极影响，可防止骨质疏松症，但增加了乳腺癌和子宫癌的风险。在中枢神经系统（CNS）中产生有益作用但缺乏E2的癌症风险特征的选择性雌激素受体调节剂（SERMS）非常需要E2的有益作用。已经提出，核雌激素受体ERα和ERβ构成了E2的所有作用，但是我们的研究为新型膜相关的E2受体提供了有力的证据，该膜相关的E2受体介导了CNS中的快速信号传导。该受体尚未被鉴定，也没有完全理解其与效应系统的耦合的性质。我们最近合成了专门针对膜受体的第一个Serm STX，这将使我们能够严格地表征并最终识别膜ER。我们的假设是，E2的快速作用是由于它与G蛋白偶联受体的结合，该受体激活激酶途径以减弱GABA-B和MU-APIER受体活性。在此提案中，我们试图阐明通过STX激活的细胞级联反应，并进一步表征介导这些作用的受体。我们将使用独特的细胞，分子和化学工具来表征GQ耦合的E2受体，其与下丘脑神经元中信号通路的耦合及其功能后果。具体目的是：（1）测试STX是否使用与E2相同的受体介导的信号通路，以从POMC和多巴胺神经元中的K+通道中脱离GABA-B和MU-Apoile受体。 （2）测试STX是否会在E2调节的转录本的亚组中改变基因表达，这对于下丘脑神经元的突触传播至关重要。 （3）在ERα和β缺陷型小鼠中是否存在E2和S TX对POMC和多巴胺神经元的快速影响，并基于结果为膜ER制定了克隆策略。这些研究不仅将确定对下丘脑神经元快速信号传导至关重要的途径，而且还应允许开发新的Serm，专门针对控制女性体内平衡的关键脑回路。