HORMONAL MODULATION OF CA2+ SOURCES IN HIPPOCAMPAL AGING AND VULNERABILITY

海马老化和脆弱性中 CA2 源的激素调节

• 批准号: 6299339
• 负责人: PHILIP W. LANDFIELD
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299339
• 关键词: 1,25 dihydroxycholecalciferol; Alzheimer's disease; aging; apoptosis; biological signal transduction; calcium channel; calcium flux; calmodulin dependent protein kinase; confocal scanning microscopy; electrophysiology; enzyme activity; estrogens; glucocorticoids; glutamates; hippocampus; hormone regulation /control mechanism; laboratory rat; neural degeneration; neurohormones; neurons; neuropharmacology; neuroregulation; neurotoxins; polymerase chain reaction; tissue /cell culture

This project developed out of studies showing that glucocorticoid (GC) hormones appeared to accelerate aspects of brain aging, neuron visibility and possibly Alzheimer's disease (AD). In addition, previous electrophysiological studies in this project found that GCs increase calcium-mediated potentials and currents (GCs are also known to influence long-term potentiation and synaptic potentials). In recent we have found that another steroid, calcitriol, also appears to influence electrophysiology and is neuroprotective. Estrogens are also known to be neuroprotective. Thus, this project will focus on identifying the electrophysiological and calcium-mediated mechanisms that underlie the effects of GCs, calcitriol and estrogens on brain aging, neuronal vulnerability and possibly Alzheimer's disease. This project will utilize two model systems, the rat hippocampal slice to study aging effects, and rat hippocampal cultured neurons, to study neuronal vulnerability. In three of the specific aims, the project will determine which electrophysiologically and pharmacologically defined currents and calcium sources are affected by the steroids, we will determine whether the effects of steroids change with aging, and will test the hypothesis that these steroid effects contribute importantly to hippocampal neuron vulnerability to glutamate-induced cell death. In two other aims, the project will attempt to identify the molecular and intracellular pathways, including those activated by kinases, that mediate steroid effects on electrophysiological properties and calcium regulation. Together, these studies are aimed at both identifying the underlying mechanisms and at clearly testing the functional relevance for aging and neurodegeneration, of steroid actions on the properties of brain neurons. These studies, therefore, should substantially clarify our understanding of the mechanisms through which brain aging and the endocrine environment increase the risk for Alzheimer's disease and other neurodegenerative disorders.

该项目的开发研究表明，糖皮质激素 (GC) 激素似乎会加速大脑老化、神经元老化 能见度和可能的阿尔茨海默病（AD）。另外，之前的 该项目中的电生理学研究发现 GC 增加 钙介导的电位和电流（GC 也被称为 影响长时程增强和突触电位）。最近我们 发现另一种类固醇，骨化三醇，似乎也影响 电生理学并具有神经保护作用。雌激素还被认为是 神经保护作用。因此，该项目将重点关注确定 电生理和钙介导的机制 GC、骨化三醇和雌激素对大脑衰老、神经元的影响 脆弱性和可能的​​阿尔茨海默病。该项目将 利用大鼠海马切片这两个模型系统来研究衰老 效应，并培养大鼠海马神经元，以研究神经元 脆弱性。在三个具体目标中，该项目将确定 它从电生理学和药理学上定义了电流和 钙来源受到类固醇的影响，我们将确定是否 类固醇的作用会随着年龄的增长而变化，并将检验这一假设 这些类固醇效应对海马神经元有重要贡献 易受谷氨酸诱导的细胞死亡的影响。在另外两个目标中， 项目将尝试识别分子和细胞内 介导类固醇的途径，包括由激酶激活的途径 对电生理特性和钙调节的影响。 总之，这些研究旨在确定潜在的 机制并明确测试衰老和功能相关性 神经退行性变，类固醇对大脑特性的作用 神经元。因此，这些研究应该能够从根本上澄清我们的 了解大脑衰老的机制 内分泌环境会增加患阿尔茨海默病的风险 其他神经退行性疾病。