DEVELOPMENTAL ACTION OF ESTROGEN ON COGNITIVE SUBSTRATES

描述（改编自申请人摘要）：本提案涉及 雌激素和神经营养因子 肽家族可以介导主要和 发育中大脑的雌激素靶区，即大脑皮层， 皮层 这些研究调查了 雌激素在大脑中的分化（促进神经突）作用， 我在发育中的大脑的器官型培养物中首次描述了这种特性。 我的实验室也是第一个证明广泛共表达的 雌激素和神经营养因子（trk）受体在发育中的中枢神经系统神经元， vivo. 我们的工作假设是这些受体的共定位 系统可能导致其配体的相互依赖性， 它们的信号转导通路的会聚。 实验研究 一个假定的大分子信号复合物的组织， 激活可导致雌激素和神经营养因子信号传导的会聚。 我们将描述所涉及的受体的身份， 雌激素和神经营养因子相互依赖的功能后果。 交叉耦合会聚雌激素和神经营养因子信号可能导致 相似的核终点和相同基因的调控。 器官型 发育中的大脑皮层的外植体（切片），来自出生后 野生型和ER-α敲除（ER-KO）小鼠，并保持为滚管 文化，将作为主要的模式系统。 神经元（PC 12; PC 12-E2） 和非神经元（MCF-7; CHO-K1）肿瘤细胞系将用作 方法和相关控制。 雌激素受体表达和 神经元分化，包括神经突生长，将作为 一些不同的反应。 将通过以下方法对培养物进行相关分析： 组织学、分子生物学、生物化学和免疫学 技术. 这些研究对整个人类社会有着深远的影响。 中枢神经系统的发展以及神经退行性疾病和神经 修复. 所获得的结果将提供新的信息， 与理解发展行动的相关性， 雌激素对大脑的神经保护作用。 了解如何 雌激素影响中枢神经系统的分化和发育， 与神经营养因子的相互作用可能有助于解释最近的发现， 雌激素可以对高级认知过程产生影响， 雌激素或其缺乏可能是发展的危险因素， 认知的性二态性障碍（学习障碍和 注意力缺陷多动障碍），神经发育障碍， 认知缺陷（精神分裂症）和神经退行性疾病 （阿尔茨海默氏病）。

DESCRIPTION (Adapted from applicant's abstract): This proposal addresses some novel and unconventional means by which estrogen and the neurotrophin family of peptides may mediate differentiative effects within a major and understudied estrogen target region of the developing brain, the cerebral cortex. The studies investigate the mechanisms underlying the differentiative (neurite-promoting) actions of estrogen in the brain, a property I first described in organotypic cultures of the developing brain. My laboratory was also the first to demonstrate widespread co-expression of the estrogen and neurotrophin (trk) receptors in developing CNS neurons in vivo. Our working hypothesis is that co-localization of these receptor systems may lead to interdependency of their ligands and the sharing or convergence of their signal transduction pathways. The experiments study the organization of a putative macromolecular signaling complex whose activation may lead to convergence of estrogen and neurotrophin signaling. We will characterize the identity of the receptors involved and the functional consequences of estrogen and neurotrophin interdependency. Cross-coupling of converging estrogen and neurotrophin signaling may lead to similar nuclear end-points and regulation of the same genes. Organotypic explants (slices) of the developing cerebral cortex, derived from postnatal wild-type and ER-alpha knockout (ER-KO) mice and maintained as roller tube cultures, will serve as the primary model system. Neuronal (PC12; PC12-E2) and non-neuronal (MCF-7; CHO-K1) tumour cell lines will serve as methodological and correlative controls. Estrogen receptor expression and neuronal differentiation, including neurite growth, will serve as markers of some differentiative responses. Cultures will be analyzed correlatively by histological, molecular biological, biochemical, and immunological techniques. These studies have profound ramifications for the overall development of the CNS as well as for neurodegenerative diseases and neural repair. The results obtained will provide new information with great relevance for understanding the developmental actions and perhaps even the neuroprotective effects of estrogen in the brain. Understanding how estrogen influences differentiation and development in the CNS through its interactions with the neurotrophins may help explain recent findings that estrogen can exert effects on higher order cognitive processes and that estrogen or its deficiency may be risk factors for the development of the sexually dimorphic disorders of cognition (learning disabilities and attention deficit hyperactivity disorder), neurodevelopment disorders with cognitive deficits (schizophrenia) and neurodegenerative disorders (Alzheimer's disease).