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

据报道，雌激素影响神经发生（新神经元形成）和祖细胞的神经元存活 成年雌性大鼠海马齿状回（DG）中的细胞。虽然17 β-雌二醇（E2）被认为是 雌激素辅助这些功能，它的研究很少，很大程度上被忽视，天然立体异构体，17 α-E2 可能是对大脑更重要的雌激素。这项提议检验了17 α-E2和 ER-X，其质膜相关受体，而不是传统的17 β-E2/核ER-α， 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 这一假说是基于我们的观察，17 α-E_2在成人内源性含量 海马DG明显高于17 β-E2和成体海马前体细胞 具有高水平的“ER-X”，而缺乏ER-α和ER-β。这表明，17 α-E2具有 在海马DG中的重要作用。该建议包括一系列相关的， 互补的体外和体内实验，以比较17 α-E2和17 β-E2在 缺血性中风后海马神经元祖细胞的神经发生和神经元存活 不同年龄的C57 BL/6 J和129/SvEV完整和卵巢切除（OVX）雌性小鼠的DG，以及其他 基因型，包括ER-α无效、芳香酶敲除（ArKO）和转基因Alsheimer小鼠。 ER-X在成体祖细胞中的表达表明，其特异性配体17 α-E2可能具有 对衰老和神经退行性疾病的治疗潜力。缺乏循环17 α-E2水平， 17 α-E2和“ER-X”不太可能是经典内分泌激素/受体系统的一部分，但可能是 局部合成并具有重要的自分泌/旁分泌脑功能。治疗的挑战是 发现如何刺激和操纵内源性祖细胞，以及如何在临床上使用 内源性脑内17 α-E2含量升高的潜在益处。结果将导致药物 无需担心ER-α介导的不良外周效应， 雌激素受体β，具有巨大的影响，更安全的激素替代策略，在绝经期和 治疗诸如阿尔茨海默病和缺血性中风的神经变性疾病，以及精神病 例如经常伴随这些疾病的严重抑郁症。

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.