ESTROGEN SIGNALING IN BRAIN DURING DEVELOPMENT AND AGING

发育和衰老过程中大脑中的雌激素信号传导

• 批准号: 2456014
• 负责人: DOMINIQUE CLAUDE TORAN-ALLERAND
• 金额: $ 19.73万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2456014
• 关键词: aging; biological signal transduction; brain; cell differentiation; cell line; developmental neurobiology; estrogen receptors; estrogens; histology; immunoprecipitation; laboratory rat; neurotrophic factors; protein tyrosine kinase; receptor expression; western blottings

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.

大脑是一生中雌激素的主要目标。 我的实验室 第一个发现雌激素可以促进生长 培养切片中轴突和树突（神经突）的分化 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。该提案解决了 雌激素可能用于介导其生长的细胞内途径 向细胞核发出促进神经突的信号。 所依据的假设 这个提议是，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，还可能 作为具有酪氨酸激酶活性的受体。 当急诊室联合时 用神经生长因子受体表达，例如神经营养蛋白 (trk) 受体，这种关联可能导致共享相似的、 如果不重叠，则为细胞内生化事件的序列。 雌激素和神经营养素信号传导的交叉偶联 途径可能导致相同的核终点和调控 非常相同的基因。 我们将使用两种器官型外植体（切片） 发育出生后大鼠前脑和神经元（PC12 和 PC12-E2）和 非神经元（MCF-7；CHO-K1）肿瘤细胞系，作为模型培养物 系统。 文化将通过各种不同的方法进行相关分析 生物化学、组织学和免疫学技术。 实验 旨在识别和表征 (I) 神经营养素信号传导 雌激素激活的蛋白质； (ii) 的路径或点 雌激素和神经营养素共同发挥作用； (三) 方面 与介导这些作用的受体的性质有关 行动； (iv) 交叉耦合的功能后果 雌激素和神经营养素信号通路对 ER 表达和 神经突生长和分化。 这些研究调查并 大脑中迄今为止尚未探索过的全新且令人兴奋的领域 雌激素在整个生命过程中的作用具有广泛的影响 阿尔茨海默病 疾病和衰老。 我们早期的研究已经提供了 使用雌激素作为预防药物的生理学原理 预防或延缓与以下疾病相关的认知障碍的治疗 这些条件。 表征可能的雌激素信号通路 或者可能不是大脑特异性的，可能会导致雌激素的合成 就像药物一样，它可以复制雌激素的积极作用 大脑，同时消除其对周围环境的许多不良影响 非神经组织。