Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease

衰老和阿尔茨海默病中的钙调神经磷酸酶和炎症信号传导过程

基本信息

批准号：
7458650
负责人：
Christopher Mark Norris
金额：
$ 25.72万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7458650
关键词：
APP gene Address Adenoviruses Age Age-Months Aging Aging-Related Process Alzheimer&apos s Disease Alzheimer&apos s disease model Amygdaloid structure Amyloid Amyloidosis Animal Model Animals Anti-Inflammatory Agents Antibodies Astrocytes Behavior Behavioral Biological Biological Assay Biological Markers Brain Brain Injuries Calcineurin Calmodulin Catalytic Domain Cell Fractionation Cell membrane Cells Cerebellum Chimeric Proteins Clinical Data Coculture Techniques Cognitive Condition Coupled Cytosol Degenerative Disorder Deposition Development Disease Elevation Gene Expression Genes Genotype Glial Fibrillary Acidic Protein Goals Hippocampus (Brain)Human Immune Immunohistochemistry Immunoprecipitation Impaired cognition In Situ Hybridization Inferior Inflammatory Inflammatory Response Kentucky Knowledge Lead Link Luciferases Lymphocyte Measures Mediator of activation protein Membrane Proteins Microscopy Modeling Molecular Mus Mutation NF-AT NFAT Pathway Nerve Degeneration Nerve Tissue Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Nuclear Nuclear Translocation Parietal Lobe Pathologic Patients Pattern Personality Phosphoric Monoester Hydrolases Phosphorylation Play Price Process Property Protein Isoforms Protein Overexpression Protein phosphatase Rattus Recruitment Activity Reporter Reporting Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Rodent Model Role Senile Plaques Signal Pathway Signal Transduction Signaling Molecule Source Specimen Staging Staining method Stains Subcellular Fractions Swimming Symptoms System T-Lymphocyte Techniques Testing Tissues Universities Up-Regulation Ursidae Family Voltage-Clamp Technics Western Blotting Work age related aged aging brain amyloid pathology behavior measurement brain tissue cell type cognitive function computerized data processing cytokine human tissue inhibitor/antagonist insight interest mouse model nervous system disorder neuroinflammation neuropsychological normal aging novel nuclear factors of activated T-cells presenilin-1 programs protein expression research study tau Proteins time use transcription factor voltage

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating and irreversible neurological disease that progressively alters personality and behavior, and destroys cognitive function. With an annual price tag exceeding 100 billion dollars, AD is also one of the nation's most costly diseases. In recent years, anti-inflammatory agents have emerged as promising compounds for delaying the onset of AD symptoms. Yet, our understanding of the mechanisms underlying neuro-immune/inflammatory (im/inf) signaling in the brain remains incomplete. The Ca2+/calmodulin dependent protein phosphatase, calcineurin, plays a critical role in im/inf signaling cascades in lymphocytes and other cell types, but has received little consideration for a similar role in nervous tissue. In the past year, we found that calcineurin activation in neuron-glia co-cultures was sufficient for recapitulating several components of the im/inf response found consistently with aging and AD, including astrocyte activation and the induction of numerous im/inf-related gene cascades. We also observed a marked and selective upregulation of calcineurin in activated astrocytes surrounding amyloid deposits in AD model mice. The long-term goal of this project is to therefore test the hypothesis that calcineurin is a critical component for the activation of im/inf signaling processes associated with AD. The first two aims will test whether activation of calcineurin and/or the calcineurin-dependent transcription factor, NFAT is necessary for im/inf signaling in astrocytes. Biologically relevant inflammatory mediators will be delivered to astrocyte- specific cultures in the presence or absence of potent calcineurin and NFAT inhibitors. The induction of im/inf markers will be assessed with Western blots, RT-PCR, and cytokine arrays. Potential Ca2+ sources for calcineurin activation in astrocytes will also be examined, along with the possibility that calcineurin amplifies its own activity by up-regulating these Ca2+ sources. Aim three will use cell fractionation, immunoprecipitation, Western blot, phosphatase activity assays, immunohistochemistry, and in situ hybridization to qualitatively and quantitatively assess changes in calcineurin signaling in AD brain specimens and/or in a rodent model of AD. Completion of these studies will greatly increase our knowledge of the role of calcineurin in neuroinflammation and AD, and may lead to the development of novel treatment strategies for this disease and other degenerative conditions where neuroinflammation is prominent.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种破坏性且不可逆转的神经系统疾病，会逐渐改变性格和行为，并破坏认知功能。 AD 每年造成的损失超过 1000 亿美元，也是美国成本最高的疾病之一。近年来，抗炎剂已成为延缓 AD 症状发作的有前景的化合物。然而，我们对大脑中神经免疫/炎症 (im/inf) 信号传导机制的理解仍然不完整。 Ca2+/钙调蛋白依赖性蛋白磷酸酶、钙调磷酸酶在淋巴细胞和其他细胞类型的 im/inf 信号级联中发挥着关键作用，但在神经组织中的类似作用却很少受到关注。去年，我们发现神经元-胶质细胞共培养物中钙调神经磷酸酶的激活足以重现与衰老和 AD 一致的 im/inf 反应的几个组成部分，包括星形胶质细胞激活和大量 im/inf 相关基因的诱导级联。我们还在 AD 模型小鼠的淀粉样沉积物周围的活化星形胶质细胞中观察到钙调磷酸酶显着且选择性上调。因此，该项目的长期目标是检验以下假设：钙调神经磷酸酶是激活与 AD 相关的 im/inf 信号传导过程的关键成分。前两个目标将测试钙调磷酸酶和/或钙调磷酸酶依赖性转录因子 NFAT 的激活是否是星形胶质细胞中 im/inf 信号传导所必需的。在存在或不存在强效钙调神经磷酸酶和 NFAT 抑制剂的情况下，生物学相关的炎症介质将被递送至星形胶质细胞特异性培养物。 im/inf 标记物的诱导将通过蛋白质印迹、RT-PCR 和细胞因子阵列进行评估。还将检查星形胶质细胞中钙调神经磷酸酶激活的潜在 Ca2+ 来源，以及钙调神经磷酸酶通过上调这些 Ca2+ 来源来增强其自身活性的可能性。目标三将使用细胞分级分离、免疫沉淀、蛋白质印迹、磷酸酶活性测定、免疫组织化学和原位杂交来定性和定量评估 AD 脑标本和/或 AD 啮齿动物模型中钙调磷酸酶信号的变化。这些研究的完成将大大增加我们对钙调神经磷酸酶在神经炎症和 AD 中作用的认识，并可能导致针对这种疾病和神经炎症突出的其他退行性疾病开发新的治疗策略。