Microglial effector pathways in the CNS

描述（由申请人提供）：小胶质细胞是中枢神经系统的免疫细胞，承担许多不同的功能角色。其中一个主要作用包括参与导致急性（如中风）或慢性（如阿尔茨海默氏症、肌萎缩性侧索硬化症、青光眼）神经退行性疾病中兴奋性神经元死亡的信号通路。我们建议在这种兴奋性毒性神经退行性变的情况下研究小胶质细胞的激活过程。鉴定和表征参与小胶质细胞激活的基因可以在中枢神经系统中产生潜在的靶点，从而合理设计新的治疗方法来干预这些疾病。我们建议使用DNA芯片技术来定义导致小胶质细胞激活的信号级联。此外，我们将利用组织纤溶酶原激活剂（tPA），这是一种丝氨酸蛋白酶，由神经元和小胶质细胞产生，并通过与小胶质细胞表面受体膜联蛋白II的相互作用介导小胶质细胞的激活。tPA将被用作解剖激活过程的工具，因为它作为细胞外触发器激活细胞内效应器。我们将分析导致小胶质细胞活化的信号通路。这组实验将为随后的药物研究确定候选靶点，以抑制或抑制活化的小胶质细胞的神经毒性。

DESCRIPTION (provided by applicant): Microglia, the immune cells of the central nervous system, undertake a number of different functional roles. One major role consists of participating in a signaling pathway that leads to excitatory neuronal death in acute (e.g., stroke), or chronic (e.g., Alzheimer's, amyotrophic lateral sclerosis, glaucoma) neurodegenerative diseases. We propose to investigate the process of microglial activation in this setting of excitotoxic neurodegeneration. Identification and characterization of genes involved in microglial activation could generate potential targets in the CNS for the rational design of new therapeutic approaches for intervention in these diseases. We propose to define, using DNA chip technology, the signaling cascades that result in microglial activation. Furthermore, we will make use of tissue plasminogen activator (tPA), a serine protease that is produced by neurons and microglia and that mediates microglial activation via interaction with a microglial cell surface receptor, annexin II. tPA will be used as a tool to dissect the process of activation, since it functions as an extracellular trigger to activate intracellular effectors. The signaling pathways that lead to microglial activation will be analyzed. This set of experiments will identify candidate targets for subsequent pharmaceutical study for inhibition or suppression of the neurotoxic properties of activated microglia.