PILOT PROJECT 2: ESTROGEN RECEPTOR SPLICE VARIANT & MENOPAUSAL DEPRESSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 一些严格的，标准化的精神病诊断研究得出结论， 抑郁症（MDD）在绝经过渡期增加。大约75%的围绝经期妇女 报告的情绪和睡眠障碍，这些障碍可能会复发，在绝经期的妇女与双相情感障碍 疾病（Parry，2008）。雌激素替代疗法导致显著（超过80%）的抗抑郁 对绝经前、围绝经期妇女有效，但对绝经后期妇女无效。的机理 绝经过渡期雌激素反应的功能、结构或机制改变仍然存在 不清楚并阐明绝经后期妇女对外源性雌激素反应丧失的性质 这是本提案的目的。 我们和其他研究小组最近鉴定了几种雌激素受体（ER）剪接变异体，包括 显性负性ER β变体，大鼠海马中的ER β 2。此外，我们的试点数据表明， 卵巢切除（OVX）21天以上大鼠海马ER β 2表达增加， OVX 5天或非OVX。与21天海马ER β 2表达增加一致 OVX大鼠是雌激素诱导的神经发生的损失，目前认为这是一个神经基础， 抗抑郁药因此，我们推测绝经期相关的ER β 2表达可能作为一种调节性的调节因子。 生物标志物，也可能是绝经相关雌激素丢失的功能开关 抗抑郁作用设计了三个具体的AIM来验证我们的假设。1)表征 卵巢切除诱导的大鼠和恒河猴脑内ER <$2亚型表达2)确定 雌激素受体2对雌激素调节的脑抗抑郁作用的影响 个脑袋3)测定ERB 2对OVX大鼠中E2调节的行为抗抑郁作用的影响。

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.