Calcium Regulation in Brain Aging and Alzheimer's Disease

描述（由申请人提供）：该申请是对一个长期计划项目的更新，该项目重点关注脑衰老和阿尔茨海默病（AD）中脑细胞钙（Ca 2+）失调的机制和后果。在以前的时期，该计划项目研究了类固醇激素（糖皮质激素，雌激素，维生素D）在加速或延缓衰老引起的Ca 2+通道和Ca 2+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，基因表达分析，以及基因分析的组织块和单细胞，已被引入到该计划项目，并揭示了更广泛的变化，神经元和神经胶质细胞的生物学过程中海马老化和AD大脑比以前认识到的。特别值得注意的是Ca 2+结合分子的S100家族的上调。这些最近的研究结果强调，该计划项目的前景应该扩大到包括相关的Ca 2+失调的其他细胞生物学途径，包括神经胶质/炎症过程的研究。 因此，在下一阶段，建议采用广泛的多学科技术方法，包括Ca 2+成像、单通道记录、基因微阵列分析、蛋白质组学/蛋白质测定、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的动物模型和人类样本，以阐明Ca 2+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，在脑老化和AD。在下一阶段，提出了新的项目，核心和实验设计，这将促进多学科合作以及对多个细胞过程之间相互作用的更广泛的视角。其中包括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。现在可用于该计划项目的多学科设备应使我们能够阐明和解决与大脑和AD相关病理学中细胞衰老过程中Ca 2+失调作用相关的主要问题。

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.