Estrogen Influences on Neural Precursor Cell Development

雌激素对神经前体细胞发育的影响

• 批准号: 6811547
• 负责人: DOMINIQUE CLAUDE TORAN-ALLERAND
• 金额: $ 22.22万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6811547
• 关键词: DNA replication; animal tissue; axon; biological signal transduction; cell cycle; cell differentiation; cell growth regulation; cell proliferation; confocal scanning microscopy; dendrites; dentate gyrus; developmental neurobiology; enzyme activity; estradiol; estrogen receptors; gene expression; hormone regulation /control mechanism; immunocytochemistry; mitogen activated protein kinase; nerve stem cell; neurogenesis; neuroregulation; phosphatidylinositol 3 kinase; receptor binding; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The proposed studies are designed to obtain preliminary data concerning the actions of estrogen on the development of progenitor cells of the adult rat hippocampal dentate gyrus. 17beta-estradiol reportedly enhances granule cell neurogenesis (the formation of new neurons) in the adult female rat hippocampal dentate gyrus. The cellular mechanisms and estrogen receptor(s) mediating this hormonal action are not known. We have shown that 17beta-estradiol and its transcriptionally inactive, natural stereoisomer 17alpha- estradiol elicit rapid and transient activation of the mitogen-activated protein kinase and phosphatidylinositol 3'-kinase-Akt signaling pathways in postnatal rodent neocortical cultures and neural progenitor cells of the adult rat hippocampal dentate gyrus. These responses appear to be mediated by a putative estrogen receptor (ER), "ER-X", which is distinct from the intranuclear estrogen receptors ER-alpha and ER-beta. "ER-X" is plasma membrane associated and developmentally regulated and returns following ischemic brain injury. Progenitor cells of the adult rat hippocampal gyrus are enriched in "ER-X" protein and lack ER-alpha and ER-beta mRNA and protein. We propose a series of integrated and complimentary cell biological and biochemical analyses to compare the actions of 17alpha and 17beta-estradiol on the development of progenitor cells. WE hypothesize that "ER-X" and 17alpha-estradiol, its preferred ligand, play an important role in the development and remodeling of the hippocampus. We will test this hypothesis by focusing on the effectiveness of 17alpha estradiol in comparison with 17beta-estradiol with respect to (i) neurogenesis, (ii) neuronal differentiation, and (iii) the intracellular signaling pathways that mediate these actions. The expression of "ER-X" in the adult hippocampal dentate gyrus suggests that its developmental role could be reactivated to enhance functional hippocampal remodeling in the course of disorders of cognition, mood, and affect, such as major depression and bipolar disorder, conditions that may be associated with estrogen, since they are more frequent in females. Unlike 17beta-estradiol, 17alpha-estradiol has little affinity for ER-alpha or ER-beta and may be more effective and therapeutically safer. The results of these experiments will enable drug development and treatment of children and adults of both sexes without fear of undesirable effects mediated by ER-alpha or ER-beta.

描述（由申请人提供）：所提议的研究旨在获得有关雌激素对成年大鼠海马齿状回祖细胞发育作用的初步数据。 据报道，17β-雌二醇可增强成年雌性大鼠海马齿状回的颗粒细胞神经发生（新神经元的形成）。 介导这种激素作用的细胞机制和雌激素受体尚不清楚。 我们已经证明，17β-雌二醇及其转录失活的天然立体异构体 17α-雌二醇在出生后啮齿动物新皮质培养物和神经祖细胞中引起丝裂原激活蛋白激酶和磷脂酰肌醇 3'-激酶-Akt 信号通路的快速瞬时激活。成年大鼠海马齿状回。 这些反应似乎是由假定的雌激素受体（ER）“ER-X”介导的，该受体与核内雌激素受体 ER-α 和 ER-β 不同。 “ER-X”与质膜相关并受发育调节，并在缺血性脑损伤后恢复。 成年大鼠海马回祖细胞富含“ER-X”蛋白，缺乏ER-α和ER-β mRNA和蛋白。 我们提出了一系列综合和互补的细胞生物学和生化分析，以比较 17α 和 17β-雌二醇对祖细胞发育的作用。 我们假设“ER-X”及其首选配体17α-雌二醇在海马体的发育和重塑中发挥重要作用。 我们将通过关注 17α 雌二醇与 17β-雌二醇在 (i) 神经发生、(ii) 神经元分化和 (iii) 介导这些作用的细胞内信号通路方面的有效性来测试这一假设。 “ER-X”在成人海马齿状回中的表达表明，在认知、情绪和情感障碍（例如重度抑郁症和躁郁症）过程中，其发育作用可以被重新激活，以增强功能性海马重塑。可能与雌激素有关，因为它们在女性中更为常见。 与 17β-雌二醇不同，17α-雌二醇对 ER-α 或 ER-β 的亲和力很小，可能更有效且治疗更安全。 这些实验的结果将使药物开发和治疗儿童和成人的男女性别成为可能，而不必担心 ER-α 或 ER-β 介导的不良反应。