The role of chemoattractant receptors in central nervous system diseases

描述(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相关性痴呆症和阿尔茨海默病(AD))的进展中起着重要作用。淀粉样斑块中大量活化的小胶质细胞的存在和中枢神经系统促炎分子水平的升高支持了趋化受体和炎症在AD发病中的作用。很明显，中枢神经系统中促炎和抗炎信号之间的平衡在AD的发生和发展中是重要的。白介素4(IL-4)和其他抗炎细胞因子，如IL-13，对小胶质细胞对淀粉样蛋白β1-42(A242)的反应有不同的调节作用，这表明IL-4和IL-13有可能调节与这种神经退行性疾病相关的炎症过程。所有这些证据促使我们推测，IL-4通过调节小胶质细胞的激活及其参与神经炎症的关键趋化受体的表达，可能对中枢神经系统的促炎刺激的有害影响起到保护作用。本研究的具体目的是：1)探讨IL-4对小胶质细胞存活和活化的影响。2)研究IL-4对巨噬细胞和小胶质细胞趋化受体的调节作用。3)进一步剖析IL-4影响小胶质细胞的信号转导途径。意义：这些目标的完成将提供对IL-4在调节神经炎症中的作用的洞察，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。公共卫生相关性：大脑中大量激活的小胶质细胞的存在支持化学吸引物受体和炎症在阿尔茨海默病(AD)发病机制中的作用。白介素4(IL-4)可能对中枢神经系统促炎刺激的有害影响起到保护作用。本项目提出的目标的完成将提供对IL-4在调节神经炎症中的作用的洞察，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。

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.