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: 6098447
• 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: 1998
• 资助国家: 美国
• 起止时间: 1998-12-02 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098447
• 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.

该项目是通过研究表明糖皮质激素（GC）的研究而发展的。 激素似乎加速了脑衰老的方面，神经元 可见性，可能是阿尔茨海默氏病（AD）。另外，以前 该项目的电生理研究发现GCS增加了 钙介导的电位和电流（GC也已知 影响长期增强和突触潜力）。在最近的我们 已经发现另一种类固醇钙三醇似乎也会影响 电生理学，是神经保护性的。雌激素也已知 神经保护性。因此，该项目将着重于确定 电生理和钙介导的机制，这些机制是 GC，钙三醇和雌激素对脑衰老，神经元的影响 脆弱性以及可能是阿尔茨海默氏病。这个项目将 利用两个模型系统，大鼠海马切片来研究衰老 效应和大鼠海马培养神经元研究神经元 脆弱性。在三个特定目标中，该项目将确定 哪些电生理和药理定义的电流以及 钙来源受类固醇的影响，我们将确定是否是否 类固醇随着衰老而变化的影响，并将检验假设 这些类固醇的作用对海马神经元有重要贡献 谷氨酸诱导的细胞死亡的脆弱性。在另外两个目标中 项目将尝试识别分子和细胞内 途径，包括介导类固醇的激酶激活的途径 对电生理特性和钙调节的影响。 这些研究共同旨在识别基础 机制，并清楚地测试与衰老的功能相关性 神经变性，类固醇对大脑特性的作用 神经元。因此，这些研究应大大阐明我们的 了解大脑衰老和 内分泌环境增加了阿尔茨海默氏病和 其他神经退行性疾病。