ROLE OF 17ALPHA-ESTRADIOL IN NEUROGENESIS & NEUROPROTECTION IN ADULT AGING BRAIN

据报道，雌激素影响神经发生(新神经元的形成)和祖细胞的神经元存活 成年雌性大鼠海马齿状回细胞。而17β-雌二醇(E_2)被认为是 雌激素，雌激素具有这种功能的雌激素，它的研究很少，也被很大程度上忽略了，天然的类固醇异构体，17pha-E2 可能是对大脑更重要的雌激素。这一提议检验了17α-E2和17Alpha-E2 ER-X，其质膜相关受体，而不是传统的17β-E_2/核ER-α和 ER-β受体系统，介导雌激素对神经发生和神经元存活的影响。这 假设是基于我们观察到的成人体内内源性17α-E_2的含量 海马区DG显著高于17β-E_2和成年海马祖细胞 ER-X水平较高，而ER-α和ER-β水平不足。这表明17α-E_2具有 在整个生命过程中，在海马体DG中起着至关重要的作用。这项建议由一系列相互关联和 体内外互补实验比较17α-E_2和17β-E_2在血管紧张素转换酶中的作用 缺血性卒中后海马祖细胞的神经发生和神经元存活 不同年龄C57BL/6J和129/SvEV完整和去卵巢(OVX)雌性小鼠的DG，以及其他 基因类型，包括ER-α零、芳香酶基因敲除(ARKO)和转基因阿尔斯海默氏病小鼠。 ER-X在成体祖细胞中的表达提示其特异性配体17α-E_2可能具有 对衰老和神经退行性疾病的治疗潜力。缺乏循环中的17α-E_2水平， 17α-E2和“ER-X”不太可能是经典的内分泌激素/受体系统的一部分，但可能是 局部合成，具有重要的自分泌/旁分泌脑功能。治疗上的挑战是 了解如何刺激和操纵内源性祖细胞，以及如何在临床上使用 内源性17α-E_2含量升高的潜在益处。结果会导致毒品 设计和治疗干预，无需担心ER-α或 ER-β，对更年期和更年期更安全的激素替代策略具有巨大的影响 治疗阿尔茨海默病和缺血性中风等神经退行性疾病，以及精神疾病 经常伴随这类障碍的障碍，如严重的抑郁症。

Estrogen reportedly influences neurogenesis (new neuron formation) and neuronal survival of progenitor cells in the adult female rat hippocampal dentate gyrus (DG). While 17beta-estradiol (E2) is believed to be the estrogen subserving such functions, its little studied and largely ignored, natural steroisomer, 17alpha-E2 may be the more important estrogen for the brain. This proposal tests the hypothesis that 17alpha-E2 and ER-X, its plasma-membrane -associated receptor, and not the traditional 17beta-E2/nuclear ER-alpha and ER-beta receptor systems, mediate the effects of estrogen on neurogenesis and neuronal survival. This hypothesis is based on our observations that the en dogenous content of 17alpha-E2 i n the adult hippocampal DG is significantly higher than that of 17beta-E2 and that adult hippocampal progenitor cells have high levels of "ER-X", while deficient in ER-alpha and ER-beta. This suggests that 17alpha-E2 has a crucial role in the hippocampal DG throughout life. This proposal consists of a series of correlative and complementary in vitro and in vivo experiments to compare the roles of 17alpha-E2 and 17beta-E2 in neurogenesis and neuronal survival, following an ischemic stroke, of the progenitor cells of the hippocampal DG of variously-aged C57BL/6J and 129/SvEV intact and ovariectomized (OVX) female mice, and other genotypes, including ER-alpha null, the aromatase knockout (ArKO) and transgenic Alsheimer's mice. Expression of ER-X in adult progenitor cells suggests that 17alpha-E2, its specific ligand, may have therapeutic potential for aging and neurodegenerative disorders. Absent circulating 17alpha-E2 levels, 17alpha-E2 and "ER-X" are unlikely to be part of a classical endocrine hormone/receptor system but may be synthesized locally and have important autocrine/paracrine brain functions. The therapeutic challenge is to discover how to stimulate and manipulate the endogenous progenitor cells, and how to make clinical use of the potential benefits of the elevated endogenous brain content of 17alpha-E2. The results will lead to drug design and therapeutic intervention without fear of undesirable peripheral effects mediated by ER-alpha or ER-beta, with enormous implications for safer hormone replacement strategies at the menopause and in the treatment of such neurodegenerative disorders as Alzheimer's disease and ischemic stroke, and psychiatric disorders such as major depression which accompanies such disorders frequently.