SMALL GRANT 2: ESTROGEN RECEPTOR SPLICE VARIANT & MENOPAUSAL DEPRESSION

小额资助 2：雌激素受体剪接变体

• 批准号: 8360510
• 负责人: Junming Wang
• 金额: $ 0.48万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360510
• 关键词: Antidepressive Agents; Behavioral; Biological Markers; Brain; Data; Disease; Dominant-Negative Mutation; Estrogen Receptor 2; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Funding; Grant; Hippocampus (Brain); Macaca mulatta; Major Depressive Disorder; Menopause; Mental Depression; Mood Disorders; National Center for Research Resources; Nature; Neurosciences; Ovariectomy; Perimenopause; Postmenopause; Principal Investigator; Protein Isoforms; Psychiatric Diagnosis; RNA Splicing; Rattus; Reporting; Research; Research Infrastructure; Resources; Sleep Disorders; Source; Time; United States National Institutes of Health; Variant; Woman; base; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供 该子项目的主要支持。 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源的子项目可能列出的总成本。 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 几项严格、标准化的精神病学诊断研究得出的结论是，易患重度抑郁症 大约 75% 的围绝经期女性的抑郁症 (MDD) 会在绝经过渡期增加。 报告的情绪和睡眠障碍，这些障碍很可能在双相情感障碍女性的更年期复发 (Parry, 2008)。雌激素替代疗法产生了显着的（超过 80%）抗抑郁效果。 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。 绝经过渡期间雌激素反应的功能、结构或机制改变仍然存在 尚不清楚并阐明绝经后晚期妇女对外源雌激素反应丧失的本质 构成了本提案的目标。 我们和其他小组最近鉴定了几种雌激素受体（ER）剪接变体，包括 大鼠海马中的显性阴性 ERbeta 变体 ERbeta2 此外，我们的试验数据表明 卵巢切除 (OVX) 超过 21 天的大鼠海马 ERbeta2 表达增加，但在 OVX 5 天或非 OVX 与海马 ERbeta2 表达增加 21 天一致。 OVX 大鼠是雌激素诱导的神经发生丧失，目前认为这是神经发生的基础 因此，我们勇敢地认为，更年期相关的 ERbeta2 表达可能作为一种药物。 生物标志物，也许还可以作为与更年期相关的雌激素损失的功能开关 设计三个具体目标来验证我们的假设。 卵巢切除术诱发的 ER¿ 2 大鼠和恒河猴大脑中的异构体表达 2) 确定 ER 的影响?? 2 E2 调节的大脑在 OVX 大鼠和非人灵长类动物中的抗抑郁作用 3) 确定 ERB2 对 OVX 大鼠 E2 调节行为抗抑郁作用的影响。