PILOT PROJECT 2: ESTROGEN RECEPTOR SPLICE VARIANT & MENOPAUSAL DEPRESSION

试点项目 2：雌激素受体剪接变体

• 批准号: 7959834
• 负责人: Junming Wang
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959834
• 关键词: Antidepressive Agents; Behavioral; Biological Markers; Brain; Computer Retrieval of Information on Scientific Projects Database; Data; Disease; Dominant-Negative Mutation; Estrogen Receptor 2; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Funding; Grant; Hippocampus (Brain); Institution; Macaca mulatta; Major Depressive Disorder; Menopause; Moods; Nature; Neurosciences; Ovariectomy; Perimenopause; Pilot Projects; Postmenopause; Protein Isoforms; Psychiatric Diagnosis; RNA Splicing; Rattus; Reporting; Research; Research Personnel; Resources; Sleep Disorders; Source; Time; United States National Institutes of Health; Variant; Woman; base; depression; depressive symptoms; design; neurogenesis; nonhuman primate; relating to nervous system; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Several rigorous, standardized psychiatric diagnoses studies conclude that vulnerability to a major depressive disorder (MDD) is increased at the time of the menopause transition. About 75% of perimenopausal women reported mood and sleep disorders and these disorders are likely to recur at menopause in women with bipolar illness (Parry, 2008). Estrogen replacement therapy resulted in significant (more than 80%) anti-depressive effects in pre-, perimenopausal women but has no effects in late post-menopausal women. The mechanism of the functional, structural or mechanistic alterations of estrogen response during menopausal transition remains unclear and elucidating the nature of the loss of response to exogenous estrogen in late post-menopausal women forms the objective of this proposal. We and other groups have recently identified several estrogen receptor (ER) splice variants including the dominant negative ERbeta variant, ERbeta2 in rat hippocampus. Further more, our pilot data demonstrated an increase of ERbeta2 expression in hippocampus of rats ovariectomized (OVX) more than 21 days, but not in those OVX for 5 days or non OVX. Coincident with increase of ERbeta2 expression in hippocampus of 21 days OVX rats is the loss of estrogen-induced neurogenesis which currently believe is a neural basis for antidepressants. Therefore, we hypothesize that menopausal related ERbeta2 expression may serve as a biomarker and perhaps also as a functional switch for the menopause-related loss of estrogen antidepressive effects. Three specific AIMs are designed to validate our hypothesis. 1) CHARACTERIZE THE OVARIECTOMY-INDUCED ER¿2 ISOFORM EXPRESSION IN BRAINS OF RATS AND RHESUS MONKEYS. 2) DETERMINE THE IMPACT OF ER¿2 ON E2-REGULATED BRAIN ANTI-DEPRESSIVE EFFECTS IN OVX RAT AND NON-HUMAN PRIMATE BRAIN. 3) DETERMINE THE IMPACT OF ERB2 ON E2-REGULATED BEHAVIORAL ANTI-DEPRESSIVE EFFECTS IN OVX RATS.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 一些严格的、标准化的精神病学诊断研究得出结论，易患抑郁症 在更年期过渡时，精神障碍(MDD)的发病率会增加。约75%的围绝经期妇女 已报告的情绪和睡眠障碍以及这些障碍很可能在患有双相情感障碍的女性更年期时复发 疾病(Parry，2008)。雌激素替代疗法显著(80%以上)抗抑郁 对绝经前、围绝经期妇女有影响，但对绝经后晚期妇女没有影响。其作用机制是 绝经过渡期间雌激素反应的功能性、结构性或机械性变化 绝经后晚期妇女对外源性雌激素反应丧失的本质不清楚和阐明 形成了这项提案的目标。 我们和其他小组最近发现了几种雌激素受体(ER)剪接变异体，包括 大鼠海马区显性负性ERβ变异体ERbeta2。此外，我们的试点数据表明， 卵巢切除21d以上大鼠海马区ERbeta2表达增加，但未见明显变化 去卵巢5天或不去卵巢的患者。与21日龄大鼠海马区ERbeta2表达增加一致 OVX大鼠失去雌激素诱导的神经发生，目前认为这是神经基础 抗抑郁药。因此，我们假设与绝经相关的ERbeta2的表达可能作为一种 生物标志物，也可能是绝经后雌激素丢失的功能开关 抗抑郁作用。我们设计了三个具体的目标来验证我们的假设。1)描述 卵巢切除诱导大鼠和恒河猴脑内ER？2亚型的表达2)确定 雌激素受体2对雌激素调节的去卵巢大鼠和非人灵长类动物脑内抗抑郁作用的影响 大脑。3)观察ERB2对去卵巢大鼠雌激素调节的行为抗抑郁作用的影响。