Estrogen Influences on Neural Precursor Cell Development

描述（由申请人提供）：拟议的研究旨在获得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，β -雌二醇可促进成年雌性大鼠海马齿状回颗粒细胞的神经发生（新神经元的形成）。细胞机制和雌激素受体介导这种激素作用尚不清楚。我们已经证明，在出生后的啮齿动物新皮质培养物和成年大鼠海马齿状回神经祖细胞中，17β -雌二醇及其转录失活的天然立体异构体17α -雌二醇可引起丝裂原激活的蛋白激酶和磷脂酰肌醇3′-激酶- akt信号通路的快速和短暂激活。这些反应似乎是由一种假定的雌激素受体（ER）“ER- x”介导的，它不同于核内雌激素受体ER- α和ER- β。“ER-X”与质膜相关，受发育调控，并在缺血性脑损伤后返回。成年大鼠海马回祖细胞富集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来比较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17 α -雌二醇在海马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 -雌二醇在以下方面的有效性来验证这一假设：(1)神经发生，(2)神经元分化，以及(3)介导这些作用的细胞内信号通路。“ER-X”在成年海马齿状回的表达表明，在认知、情绪和情感障碍（如重度抑郁症和双相情感障碍）的过程中，其发育作用可能被重新激活，以增强海马功能重塑，这些疾病可能与雌激素有关，因为它们在女性中更常见。与17 -雌二醇不同，17 -雌二醇对er - α或er - β几乎没有亲和力，可能更有效，治疗上更安全。这些实验的结果将使儿童和成人的药物开发和治疗成为可能，而不必担心由er - α或er - β介导的不良影响。

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.