ESTROGEN SIGNALING IN BRAIN DURING DEVELOPMENT AND AGING

大脑是雌激素一生中的主要目标。 我的实验室 是第一个发现雌激素能促进生长的人， 分化的轴突和树突（神经突）在培养切片的 发育中的前脑以及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。该提案针对 雌激素可用于介导其生长的细胞内途径-或 促进神经突的信号传递到细胞核。 这背后的假设 这一提议是，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， 作为具有酪氨酸激酶活性的受体。 当一个人的时候， 与神经生长因子受体，如神经营养因子 (trk)受体，这种关联可能导致类似的共享， 如果不重叠的话，细胞内生化事件的序列。 会聚性雌激素和神经营养因子信号传导的交叉偶联 途径可能导致相同的核终点和调节 相同的基因。 我们将使用两种器官型外植体（切片）， 发育中的出生后大鼠前脑和神经元（PC 12和PC 12-E2）， 非神经元（MCF-7; CHO-K1）肿瘤细胞系，作为模型培养物 系统. 培养物将通过各种相关分析 生物化学、组织学和免疫学技术。 实验 设计用于识别和表征（I）神经营养因子信号传导 由雌激素激活的蛋白质;（ii） 雌激素和神经营养因子共享的会聚;（iii）方面 与参与介导这些的受体的性质有关， 行动;和（四）交叉耦合的功能后果， 雌激素和神经营养因子信号通路的ER表达和 轴突生长和分化。 这些研究调查和 一个全新的、令人兴奋的大脑区域， 对雌激素在整个生命过程中的作用有广泛的影响 的疾病和衰老。 我们早期的研究已经提供了一个 使用雌激素作为预防药物的生理学原理 治疗以预防或延缓与以下疾病相关的认知障碍： 了以下条件 表征雌激素信号通路， 或者可能不是大脑特异性的，可能会导致雌激素的合成， 比如药物，它可以复制雌激素的积极属性， 大脑，同时消除其许多不可取的周边影响， 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.