The role of chemoattractant receptors in central nervous system diseases

趋化受体在中枢神经系统疾病中的作用

• 批准号: 7499431
• 负责人: PABLO IRIBARREN
• 金额: $ 5.02万
• 依托单位: NATIONAL RESEARCH COUNCIL OF ARGENTINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499431
• 关键词: AIDS Dementia Complex; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Blood Vessels; Brain; CX3CL1 gene; Cell Death Induction; Cell Line; Central Nervous System Diseases; Central Nervous System Infections; Chemotaxis; Condition; Data; Deposition; Development; Down-Regulation; Equilibrium; Filament; Fractalkine; Gliosis; Goals; Homologous Gene; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Lesion; Ligands; Mediating; Microglia; Molecular Target; Mus; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Numbers; Oxygen; Pathogenesis; Patients; Peptides; Peripheral; Play; Process; Public Health; Regulation; Regulatory Pathway; Role; Senile Plaques; Signal Pathway; Signal Transduction; Site; Stimulus; Synapses; Therapeutic; Transcriptional Activation; Up-Regulation; chemokine; cytokine; fMet-Leu-Phe receptor; human CX3CR1 protein; insight; leukocyte activation; macrophage; mannose receptor; monocyte; neuroinflammation; neurotoxicity; receptor function; receptor mediated endocytosis; response; tau Proteins; tau mutation

DESCRIPTION (provided by applicant): Inflammation plays an important role in central nervous system (CNS) infection and the progression of neurodegenerative diseases such as HIV-associated dementia and Alzheimer's disease (AD). The presence of an abundant number of activated microglial cells in amyloid plaques and the elevated levels of pro-inflammatory molecules in CNS support the contribution of chemoattractant receptors and inflammation to the pathogenesis of AD. It is clear that a balance between pro- and anti-inflammatory signals in the CNS is important in the initiation and progression of AD. Interleukin 4 (IL-4) and other anti-inflammatory cytokines, such as IL-13, differentially regulate microglial responses to amyloid beta 1-42 (A242), the pathogenic peptide in AD; which indicates that IL-4 and IL-13 have the potential to regulate inflammatory processes associated with this neurodegenerative disease. All these evidences prompted us to hypothesize that IL-4, by regulating the activation of microglial cells and its expression of key chemoattractant receptors that participate in neuroinflammation, may provide protection against the deleterious effects of proinflammatory stimuli in the CNS. The specific aims of this study are: 1) To evaluate the effects of IL-4 on the survival and activation of microglial cells. 2) To examine the regulation of chemoattractant receptors in macrophages and microglia by interleukin 4. 3) To further dissect the signaling pathways involved in the effects of IL-4 on microglial cells. Significance: The completion of these goals will provide insights into the role of IL-4 in the regulation of neuroinflammation and the definition of potential molecular targets for the development of therapeutic approaches to treat AD and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The presence of an abundant number of activated microglial cells in the brain support the contribution of chemoattractant receptors and inflammation to the pathogenesis of Alzheimer's disease (AD). Interleukin 4 (IL- 4) may provide protection against the deleterious effects of pro-inflammatory stimuli in the central nervous system. The completion of the goals proposed in this project will provide insights into the role of IL-4 in the regulation of neuroinflammation and the definition of potential molecular targets for the development of therapeutic approaches to treat AD and other neurodegenerative diseases.

描述（由申请人提供）：炎症在中枢神经系统（CNS）感染和神经退行性疾病（如HIV相关痴呆和阿尔茨海默病（AD））的进展中起重要作用。淀粉样斑块中大量活化的小胶质细胞的存在和CNS中促炎分子水平的升高支持了化学引诱物受体和炎症对AD发病机制的贡献。很明显，CNS中促炎信号和抗炎信号之间的平衡在AD的起始和进展中是重要的。白细胞介素4（IL-4）和其他抗炎细胞因子，如IL-13，差异调节小胶质细胞对淀粉样蛋白β 1-42（A242）的反应，淀粉样蛋白β 1 - 42是AD中的致病肽;这表明IL-4和IL-13具有调节与这种神经退行性疾病相关的炎症过程的潜力。所有这些证据促使我们假设IL-4通过调节小胶质细胞的活化及其参与神经炎症的关键化学引诱物受体的表达，可以提供对CNS中促炎刺激的有害作用的保护。本研究的具体目的是：1）观察IL-4对小胶质细胞存活和活化的影响。2)研究白细胞介素4对巨噬细胞和小胶质细胞趋化因子受体的调节作用。3)进一步探讨IL-4对小胶质细胞作用的信号通路。重要性：这些目标的完成将提供对IL-4在神经炎症调节中的作用的深入了解，并为开发治疗AD和神经退行性疾病的治疗方法定义潜在的分子靶点。公共卫生关系：大脑中大量活化的小胶质细胞的存在支持了化学引诱物受体和炎症对阿尔茨海默病（AD）发病机制的贡献。白细胞介素4（IL- 4）可以提供保护免受中枢神经系统中促炎刺激的有害作用。该项目中提出的目标的完成将为IL-4在神经炎症调节中的作用提供见解，并为开发治疗AD和其他神经退行性疾病的治疗方法定义潜在的分子靶点。