Calcium Regulation: Brain Aging/Alzheimer's Disease

描述（由申请人提供）：本申请是一个长期项目项目的更新，该项目专注于大脑衰老和阿尔茨海默病（AD）中脑细胞钙（Ca2+）失调的机制和后果。在之前的阶段，该项目研究了类固醇激素（糖皮质激素、雌激素、维生素D）在加速或延缓衰老诱导的Ca2+通道和Ca2+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失调和神经元易感性中的作用。此外，在过去几年中，新的基因表达分析的统计方法，以及组织块和单细胞的基因谱，已经被引入到项目中，并揭示了海马老化和AD大脑中神经元和神经胶质细胞生物学过程的变化比以前认识到的要广泛得多。特别值得注意的是Ca2+结合分子S100家族的上调。这些最近的发现强调，该计划项目的观点应该扩大到包括Ca2+失调与其他细胞生物学途径的研究，包括神经胶质/炎症过程。

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.