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.
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