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

17α-雌二醇在神经发生中的作用

• 批准号: 7246204
• 负责人: DOMINIQUE ALLERAND
• 金额: $ 28.36万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246204
• 关键词: 17p; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Antibodies; Antidepressive Agents; Aromatase; Astrocytes; Biological Assay; Biology; Brain; Bromodeoxyuridine; C57BL/6 Mouse; Cell Count; Cell Nucleus; Cell Proliferation; Cell division; Cell membrane; Cells; Chromatin; Clinical; Cognitive deficits; Count; DNA Fragmentation; DNA biosynthesis; DNA chemical synthesis; Daily; Disease; Drug Design; Employee Strikes; Endocrine; Enzyme-Linked Immunosorbent Assay; Enzymes; Estradiol; Estrogen Receptors; Estrogens; Estrone; Exhibits; Female; Figs - dietary; Fright; Genotype; Goals; Hippocampus (Brain); Histone H3; Hormone Receptor; Hormones; In Situ; In Situ Nick-End Labeling; In Vitro; Ischemic Stroke; Isomerism; Knock-out; Label; Lead; Life; Ligands; Liquid Chromatography; Major Depressive Disorder; Mediating; Memory impairment; Menopause; Mental disorders; Mitotic spindle; Mus; Neocortex; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Nuclear Antigens; Nuclear Receptors; Oligodendroglia; Optics; Ovariectomy; Oxidative Stress; Pattern; Peripheral; Phenotype; Physical condensation; Play; Proliferating; Property; Proteins; Radial; Rate; Rattus; Reporting; Role; S Phase; Series; Staining method; Stains; Stem cells; Stroke; System; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; Week; age related; aged; aging brain; autocrine; base; cognitive function; dentate gyrus; fluoro jade; human ESR1 protein; in vivo; middle age; nestin protein; neurogenesis; neuronal survival; neuroprotection; paracrine; receptor; research study; response; senescence; sex; tandem mass spectrometry

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.

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 17β-雌二醇 (E2) 被认为是 雌激素促进此类功能，但对其研究很少且基本上被忽视，天然立体异构体，17α-E2 可能是对大脑更重要的雌激素。该提案检验了以下假设：17alpha-E2 和 ER-X，其质膜相关受体，而不是传统的 17β-E2/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 假设基于我们的观察，即成人体内 17α-E2 的内源含量 海马 DG 显着高于 17β-E2 且成年海马祖细胞 具有高水平的“ER-X”，但缺乏 ER-α 和 ER-β。这表明 17α-E2 具有 海马 DG 在整个生命过程中发挥着至关重要的作用。该提案由一系列相关的和 互补的体外和体内实验来比较 17α-E2 和 17β-E2 在 缺血性中风后海马祖细胞的神经发生和神经元存活 不同年龄的 C57BL/6J 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 缺失、芳香酶敲除 (ArKO) 和转基因阿尔斯海默氏小鼠。 ER-X 在成体祖细胞中的表达表明，其特异性配体 17α-E2 可能具有 衰老和神经退行性疾病的治疗潜力。缺乏循环 17α-E2 水平， 17α-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。治疗挑战是 发现如何刺激和操纵内源性祖细胞，以及如何临床应用 17α-E2 内源性大脑含量升高的潜在好处。结果将导致药物 设计和治疗干预，无需担心 ER-α 或介导的不良外周效应 ER-β，对更年期和更年期更安全的激素替代策略具有巨大影响 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科疾病 疾病，例如经常伴随此类疾病的重度抑郁症。