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Calcium Regulation in Brain Aging & Alzheimer's Disease

大脑衰老中的钙调节

基本信息

批准号：
7544617
负责人：
PHILIP W. LANDFIELD
金额：
$ 10.99万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-02 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544617
关键词：
Accounting Address Affect Age Aging Aging-Related Process Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Animals Behavior Behavioral Assay Binding Biochemical Biological Biological Markers Biological Process Brain Budgets Buffers Calcium Calpain Cell Aging Cell Death Cell physiology Cells Cellular Structures Cognitive Collaborations Complex Data Development Disease Electrophysiology (science)Elevation Estrogens Experimental Designs Family Fire - disasters Fruit Functional disorder Gene Expression Gene Transfer Generations Genes Glucocorticoids Goals Growth Factor Hippocampus (Brain)Homeostasis Human Image Imaging Techniques Immunohistochemistry Impairment In Situ Hybridization Individual Inflammation Inflammatory Interdisciplinary Study Intervention Investigation Knowledge Laboratories Measures Mediating Microarray Analysis Microglia Mitochondria Modeling Molecular Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nitric Oxide Synthase Oxidative Phosphorylation Oxidative Stress Pathology Pathway interactions Pattern Performance Phase Physiological Physiological Processes Physiology Play Process Program Research Project Grants Proteins Proteomics Range Rattus Reactive Oxygen Species Regulation Research Research Personnel Resource Sharing Resources Role Sampling Second Messenger Systems Signal Pathway Signal Transduction Steroid Receptors Steroids Study models Sum Technology Testing Tissues Up-Regulation Ursidae Family Viral Vitamin D Work age effect age related aging brain base brain cell cell type cholesterol biosynthesis design indexing interdisciplinary approach middle age mitochondrial dysfunction multicatalytic endopeptidase complex multidisciplinary normal aging programs research study response second messenger steroid hormone transgenic model of alzheimer disease voltage

项目摘要

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（由申请人提供）：本申请是对一项长期计划项目的更新，该项目专注于脑老化和阿尔茨海默病（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，在过去的几年里，基因表达分析的新统计方法以及组织块和单细胞的基因分析已被引入该计划项目，并揭示了海马衰老和AD中神经元和神经胶质细胞生物学过程的更广泛变化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。