Aging microglia-neuronal communication

衰老的小胶质细胞-神经元通讯

• 批准号: 8133020
• 负责人: Gary L. Wenk
• 金额: $ 25.74万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133020
• 关键词: 8 year old; Affinity; Age; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Astrocytes; Attenuated; Biological Markers; Brain; Brain region; CCL21 gene; CD 200; CD22 gene; CD4 Positive T Lymphocytes; CXC chemokine receptor 3; Caffeine; Calcineurin; Calcium; Calcium Signaling; Calcium ion; Cells; Child; Chronic; Communication; Complex; Craniocerebral Trauma; Data; Degenerative Disorder; Disease; Dose; Down-Regulation; Elderly; Encephalitis; Environment; Enzymes; Equilibrium; Exposure to; Failure; Female; Free Radicals; Genes; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Growth; Helper-Inducer T-Lymphocyte; Hippocampus (Brain); Impaired cognition; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Interferons; Interleukins; Intraventricular Infusion; Investigation; Lead; Ligands; Lipopolysaccharides; Mediating; Memantine; Memory; Messenger RNA; Microglia; Morphology; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Neuropil; Nitric Oxide; PTPRC gene; Pathogenesis; Pattern; Phagocytosis; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Prefrontal Cortex; Process; Production; Property; Proteins; Purinergic P1 Receptors; Rattus; Receptor Activation; Recovery; Regulation; Resolution; Role; Series; Signal Transduction; Site; Stimulus; Surface; Testing; Time; Tumor Necrosis Factor-alpha; Variant; age related; aged; aging brain; atorvastatin; base; brain cell; chemokine; cingulate gyrus; combat; controlled release; cytokine; design; effective therapy; entorhinal cortex; falls; improved; injured; insight; male; nervous system disorder; neuroinflammation; normal aging; prevent; protein aggregate; receptor; release of sequestered calcium ion into cytoplasm; repaired; research study; response; uptake; young adult

DESCRIPTION (provided by applicant): The overall goal of this project is to define the glia phenotype that promotes the establishment of neurodegenerative disease states. The proposed experiments will establish a detailed understanding of age-related changes in glial activation states and how they are influenced by a neuroinflammatory stimulus. The primary focus of these studies is the interaction of microglia with neurons. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases. Subtle micro-environmental alterations can induce microglia to react rapidly, change morphology and acquire an array of functions, including phagocytosis and the secretion of inflammatory molecules. The consequences of this activation must be tightly regulated because both inadequate and excessive responses can result in pathological consequences. The balance of these processes, operating across a time scale of decades, are carefully orchestrated and regulated until, due to normal aging, there is a gradual shift to a non-equilibrium state that is permissive for neurodegenerative processes. Aim 1 will determine the time course and regional changes in phenotype profile of the microglial activation associated with normal aging or the intraventricular infusion of LPS using a series of markers that discriminate pro- or anti-inflammatory microglia states. Aim 2 will investigate three specific mechanisms by which neurons regulate the microglial cytokine profile, the response of these mechanisms to challenge by LPS and how they are altered by normal aging. Aim 3 will examine the ability of caffeine to restore cytokine balance and promote an anti-inflammatory cytokine profile in young and aged male rats and improve spatial memory. Aim 4 will investigate the consequences of inflammation-induced alterations in NMDA-type glutamate receptor- dependent calcium ion signaling. We hypothesize that the pattern of these changes, and the degenerative changes that subsequently develop, may be due to regional variations in the micro-environment that are a direct consequence of the ability of activated microglia or injured neurons to release pro- and anti-inflammatory molecules in response to their age and ability to communicate with neurons.

描述（由申请人提供）：本项目的总体目标是确定促进神经退行性疾病状态建立的神经胶质细胞表型。拟议的实验将建立一个详细的了解年龄相关的变化，神经胶质细胞激活状态，以及它们是如何影响神经炎症刺激。这些研究的主要焦点是小胶质细胞与神经元的相互作用。脑细胞间的相互作用可能是理解神经退行性疾病发病机制中炎症机制的关键。微小的微环境改变可以诱导小胶质细胞快速反应，改变形态并获得一系列功能，包括吞噬作用和分泌炎性分子。这种激活的后果必须受到严格的调控，因为不充分和过度的反应都可能导致病理后果。这些过程的平衡，在几十年的时间尺度上运行，被精心策划和调节，直到由于正常的衰老，逐渐转变为允许神经退行性过程的非平衡状态。目的1将使用一系列区分促炎性或抗炎性小胶质细胞状态的标志物来确定与正常老化或LPS脑室内输注相关的小胶质细胞活化的表型特征的时程和区域变化。目的2将研究神经元调节小胶质细胞细胞因子谱的三种特定机制，这些机制对LPS攻击的反应以及它们如何被正常衰老改变。目的3将检测咖啡因恢复年轻和老年雄性大鼠细胞因子平衡和促进抗炎细胞因子谱以及改善空间记忆的能力。目的4将研究炎症诱导的NMDA型谷氨酸受体依赖的钙离子信号转导改变的后果。我们假设这些变化的模式，以及随后发展的退行性变化，可能是由于微环境的区域变化，这是激活的小胶质细胞或受损神经元释放促炎和抗炎分子的能力的直接后果，以响应其年龄和与神经元的通信能力。