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：
7643833
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/7643833
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 Brain Brain Injuries Calcineurin Calmodulin Catalytic Domain Cell Fractionation Cell membrane Cells Cerebellum Chimeric Proteins Clinical Data Coculture Techniques Cognitive Coupled Cytosol Degenerative Disorder Deposition Development Disease Gene Expression Genes Genotype Glial Fibrillary Acidic Protein Goals Hippocampus (Brain)Human Immune Immunohistochemistry Immunoprecipitation Impaired cognition In Situ Hybridization Inferior Inflammation Mediators Inflammatory Inflammatory Response Kentucky Knowledge Lead Link Luciferases Lymphocyte Measures Membrane Proteins Microscopy Modeling Molecular Mus Mutation 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 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 aging brain amyloid pathology behavior measurement brain tissue cell type cognitive function computerized data processing cytokine human tissue inflammatory marker inhibitor/antagonist insight interest molecular marker mouse model nervous system disorder neuroinflammation neuropsychological normal aging novel nuclear factors of activated T-cells overexpression presenilin-1 programs protein expression research study tau Proteins time use transcription factor treatment strategy voltage

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 Brain Brain Injuries Calcineurin Calmodulin Catalytic Domain Cell Fractionation Cell membrane Cells Cerebellum Chimeric Proteins Clinical Data Coculture Techniques Cognitive Coupled Cytosol Degenerative Disorder Deposition Development Disease Gene Expression Genes Genotype Glial Fibrillary Acidic Protein Goals Hippocampus (Brain)Human Immune Immunohistochemistry Immunoprecipitation Impaired cognition In Situ Hybridization Inferior Inflammation Mediators Inflammatory Inflammatory Response Kentucky Knowledge Lead Link Luciferases Lymphocyte Measures Membrane Proteins Microscopy Modeling Molecular Mus Mutation 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 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 aging brain amyloid pathology behavior measurement brain tissue cell type cognitive function computerized data processing cytokine human tissue inflammatory marker inhibitor/antagonist insight interest molecular marker mouse model nervous system disorder neuroinflammation neuropsychological normal aging novel nuclear factors of activated T-cells overexpression presenilin-1 programs protein expression research study tau Proteins time use transcription factor treatment strategy voltage

展开

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）是一种毁灭性且不可逆转的神经系统疾病，逐渐改变了人格和行为，并破坏了认知功能。 AD的年价格超过1000亿美元，也是美国最昂贵的疾病之一。近年来，抗炎剂已成为延迟AD症状发作的有希望的化合物。然而，我们对大脑中神经免疫/炎症（IM/INF）信号的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神经蛋白在淋巴细胞和其他细胞类型的IM/INF信号级联反应中起着至关重要的作用，但几乎没有考虑到在神经组织中的相似作用。在过去的一年中，我们发现神经元-GLIA共培养中的钙调蛋白激活足以概括与衰老和AD始终发现的IM/INF反应的几个成分，包括星形胶质细胞激活以及诱导许多IM/INF相关基因级联。我们还观察到在AD模型小鼠的淀粉样蛋白沉积物周围活化的星形胶质细胞中钙调蛋白的明显和选择性上调。因此，该项目的长期目标是检验以下假设：钙调蛋白是激活与AD相关的IM/INF信号过程的关键组成部分。前两个目标将测试钙调神经磷酸酶和/或钙调神经素依赖性转录因子是否激活NFAT对于星形胶质细胞中的IM/INF信号是必需的。在存在或不存在有效的钙调蛋白和NFAT抑制剂的情况下，与生物学相关的炎症介质将被递送至星形胶质细胞培养物。 IM/INF标记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蛋白激活的潜在Ca2+来源，并通过上调这些CA2+来源来扩大钙调神经素的可能性。 AIM三将使用细胞分馏，免疫沉淀，蛋白质印迹，磷酸酶活性测定，免疫组织化学以及原位杂交来定性，定量地评估AD脑标本和/或AD啮齿动物模型中钙调神经磷酸酶信号传导的变化。这些研究的完成将大大提高我们对钙调神经酶在神经炎症和AD中的作用的了解，并可能导致针对这种疾病的新型治疗策略以及神经炎症很突出的其他退行性疾病的发展。