ESTROGEN SIGNALING IN BRAIN DURING DEVELOPMENT AND AGING

大脑是雌激素一生中的主要靶子。我的实验室 是第一个发现雌激素促进生长和 培养脑片中轴突和树突(神经突起)的分化 发育中的前脑与雌激素和神经营养素受体 共同定位于发育中的前脑神经元。这项建议解决了 雌激素可能用来调节其生长的细胞内途径-或 促进神经突起的信号传给细胞核。其背后的假设 这一建议是发育中的大脑中的雌激素受体(ER) 可能不仅仅是配体诱导的转录增强子，还可能 作为一种具有酪氨酸激酶活性的受体。当急诊室联合- 表达神经生长因子受体，如神经营养因子 (Trk)受体，这种联系可能导致类似的， 如果不重叠，细胞内生化事件的序列。 雌激素与神经营养因子信号的交叉偶联 途径可能导致相同的核终点和调节 完全相同的基因。我们将使用两种器官类型外植体(切片) 出生后发育的大鼠前脑和神经元(PC12和PC12-E2)和 非神经性(MCF-7；CHO-K1)肿瘤细胞系作为模型培养 系统。文化将通过各种不同的 生化、组织学和免疫学技术。这些实验 旨在识别和表征(I)神经营养因子信号 由雌激素激活的蛋白质；(Ii)雌激素的途径或点 雌激素和神经营养素的趋同；(Iii)方面 与参与调节这些活动的受体的性质有关 行动；和(Iv)交叉耦合的功能后果 雌激素和神经营养素信号转导途径对ER表达的影响 轴突的生长和分化。这些研究调查和 全新的和令人兴奋的区域，这是迄今为止在大脑中从未探索过的 对阿尔茨海默病患者一生中的雌激素作用有广泛的影响 S病，又有抗衰老作用。我们早期的研究已经提供了一个 使用雌激素作为预防措施的生理学基础 预防或延缓与以下相关的认知障碍的治疗 这些条件。表征雌激素信号通路可能 或者可能不是大脑特有的，可能导致雌激素的合成- 比如药物，它可以复制雌激素的积极属性 大脑，同时消除它的许多不良的外围影响 非神经组织。

The brain is a major target of estrogen throughout life. My laboratory was the first to discover that estrogen enhances the growth and differentiation of axons and dendrites (neurites) in cultured slices of the developing forebrain and that estrogen and neurotrophin receptors co-localize in developing forebrain neurons. This proposal addresses the intracellular pathways estrogen may use in mediating its growth-or neurite-promoting signals to the nucleus. The hypothesis underlying this proposal is that the estrogen receptor (ER) in the developing brain may be more than a ligand-induced transcriptional enhancer and may also act as a receptor with tyrosine kinase activity. When the ER is co- expressed with neural growth factor receptors, such as the neurotrophin (trk) receptors, this association may lead to the sharing of similar, if not overlapping, sequences of intracellular biochemical events. Cross-coupling of converging estrogen and neurotrophin signaling pathways may lead to the same nuclear end-points and regulation of the very same genes. We will use both organotypic explants (slices) of developing postnatal rat forebrain and neuronal (PC12 and PC12-E2) and non-neuronal (MCF-7; CHO-K1) tumour cell lines, as model culture systems. Cultures will be analyzed correlatively by a variety of biochemical, histological and immunological techniques. The experiments are designed to identify and characterize (I) neurotrophin signaling proteins activated by estrogen; (ii) the pathways or points of convergence shared by estrogen and the neurotrophins; (iii) aspects related to the nature of the receptors involved in mediating these actions; and (iv) the functional consequences of cross coupling of estrogen and neurotrophin signaling pathways for ER expression and neurite growth and differentiation. These studies investigate and entirely new and exciting area heretofore unexplored in the brain and have broad implications for estrogen actions throughout life Alzheimer s disease and for aging. Our earlier studies have already provided a physiological rationale for the use of estrogen as a prophylactic treatment to prevent or retard the cognitive disorders associated with these conditions. Characterizing estrogen signaling pathways that may or may not be brain-specific could lead to the synthesis of estrogen- like drugs, which could duplicate estrogen's positive attributes for the brain, while eliminating many of its undesirable peripheral effects on non-neural tissues.