Microglial effector pathways in health and disease

描述（由申请人提供）：小胶质细胞是中枢神经系统的免疫活性细胞，与神经元相互作用，并承担许多不同的功能作用，这些功能作用被认为有助于急性（例如，中风），或慢性（例如，阿尔茨海默氏症、肌萎缩侧索硬化症、青光眼）神经变性疾病。我们建议调查的信号通路，导致从神经元损伤的小胶质细胞激活的兴奋毒性神经变性模型。我们建议的特点，吸引小胶质细胞的神经元损伤部位的趋化梯度，并定义导致小胶质细胞激活的信号级联。我们将利用组织纤溶酶原激活剂（tPA），一种由神经元和小胶质细胞产生的丝氨酸蛋白酶，通过与小胶质细胞表面结合伴侣膜联蛋白A2相互作用介导小胶质细胞活化。我们还将分析tPA /膜联蛋白A2依赖性小胶质细胞激活和血脑屏障损害后的效应途径。最后，我们将使用小胶质细胞无功能的动物，以及在小胶质细胞和双光子显微镜中表达EGFP的小鼠来研究小胶质细胞在CNS正常非病理功能中的作用。 这是一项杰出的提案，将研究信号，以确定小胶质细胞在兴奋性毒性后是神经保护性的还是神经毒性的。该提案的优点包括调查员在上一个供资周期的工作效率。这项研究的结果可能会对小胶质细胞和炎症细胞的研究做出重大贡献。

Description (provided by the applicant): Microglia, the immunocompetent cells of the central nervous system, interact with neurons and undertake a number of different functional roles thought to contribute 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 signaling pathways that lead from neuronal insult to microglial activation in a model of excitotoxic neurodegeneration. We propose to characterize the chemotactic gradients that attract microglia to sites of neuronal injury and define the signaling cascades that result in microglial activation. We will make use of tissue plasminogen activator (tPA), a serine protease produced by neurons and microglia that mediates microglial activation via interaction with a microglial cell surface binding partner, annexin A2. We will also analyze the effector pathways that follow tPA / annexin A2-dependent microglial activation and compromise of the blood-brain-barrier. Finally, we will use animals whose microglia are non functional, as well as mice that express EGFP in their microglia and two-photon microscopy to investigate the role of microglia in normal, non-pathological functions in the CNS. outstanding proposal that will investigate the signals the determine whether microglia are neuroprotective or neurotoxic following excitotoxicity. The strengths of the proposal include the productivity of the investigator during the previous funding cycle,. The findings of this study could make a significant contribution to the study of microglia and inflammatory cells in general.