Calcium Regulation in Brain Aging and Alzheimer's Disease

大脑衰老和阿尔茨海默病中的钙调节

• 批准号: 7475683
• 负责人: PHILIP W. LANDFIELD
• 金额: $ 162.15万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475683
• 关键词: Calcium; Regulation; Brain; Aging; Alzheimer

DESCRIPTION (provided by applicant): This application is for a renewal of a longstanding program project focused on mechanisms and consequences of brain cell calcium (Ca2+) dysregulation in brain aging and Alzheimer's disease (AD). In prior periods, the program project has studied the role of steroid hormones (glucocorticoids, estrogen, vitamin D) in accelerating or retarding aging-induced changes in Ca2+ channels and Ca2+ homeostasis. The program project has also investigated the roles of reactive oxygen species (ROS), AD-related mutations and mitochondrial dysfunction in Ca+2 dysregulation and neuronal vulnerability. Moreover, in the past few years, new statistical approaches to gene expression analysis, as well as gene profiling of tissue blocks and single cells, have been introduced into the program project, and revealed much wider alterations of neuronal and glial cell biological processes in hippocampal aging and AD brain than was previously recognized. Particularly notable was an upregulation of S100 family of Ca2+ binding molecules. These recent findings emphasize that the perspectives of the program project should be broadened to encompass studies relating Ca2+ dysregulation to other cell biological pathways, including glial/inflammatory processes. In the next phase, therefore, it is proposed to bring to bear a wide range of multidisciplinary technical approaches, including Ca2+ imaging, single channel recording, gene microarray analyses, proteomics/protein assays, behavioral analyses, oxidative stress indexes, viral mediated gene transfer and in situ hybridization/immunohistochemistry, using animal models of aging/AD and human samples, to elucidate interactions between Ca2+ dysregulation, steroid modulation, gene expression cascades, oxidative stress and mitochondrial dysfunction, in brain aging and AD. In the next phase, new projects, cores and experimental designs are proposed that will facilitate multidisciplinary collaboration as well as a broader perspective on interactions among multiple cellular processes. Included among these are cores that will support analyses of inflammatory mechanisms and long-term intervention tests of hypotheses arising from individual projects. The multidisciplinary armamentarium now available to the program project should enable us to elucidate and resolve the major questions related to the roles of Ca2+ dysregulation in cellular aging processes in the brain and AD-related pathology.

描述(申请人提供)：本申请是一个长期项目的续展，该项目重点关注脑细胞钙(Ca~(2+))失调在脑老化和阿尔茨海默病(AD)中的机制和后果。在之前的阶段，该项目已经研究了类固醇激素(糖皮质激素、雌激素、维生素D)在加速或延缓衰老引起的钙通道和钙稳态变化中的作用。该项目还研究了活性氧(ROS)、AD相关突变和线粒体功能障碍在Ca+2失调和神经元脆弱性中的作用。此外，在过去的几年中，新的统计方法用于基因表达分析，以及组织块和单细胞的基因图谱，并揭示了海马区衰老和AD脑中神经元和神经胶质细胞生物学过程的变化比先前认识的要广泛得多。尤其值得注意的是，S100家族的钙结合分子表达上调。这些最近的发现强调，该计划项目的视角应该扩大到包括与钙离子失调与其他细胞生物学途径有关的研究，包括神经胶质/炎症过程。 因此，在下一阶段，建议采用广泛的多学科技术手段，包括钙离子成像、单通道记录、基因芯片分析、蛋白质组学/蛋白质分析、行为分析、氧化应激指数、病毒介导的基因转移和原位杂交/免疫组织化学，使用衰老/AD动物模型和人类样本，以阐明脑老化和AD中钙离子调节失调、类固醇调节、基因表达级联、氧化应激和线粒体功能障碍之间的相互作用。在下一阶段，将提出新的项目、核心和实验设计，以促进多学科合作，并就多个细胞过程之间的相互作用提供更广阔的视角。其中包括将支持炎症机制分析和对个别项目产生的假设进行长期干预测试的核心。该项目目前提供的多学科设备应使我们能够阐明和解决与脑细胞衰老过程中钙离子调节异常的作用相关的主要问题和AD相关的病理。