Microglial effector pathways in health and disease

描述(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，承担许多不同的功能，被认为是急性(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)神经退行性疾病中兴奋性神经元死亡的原因。我们建议在兴奋性神经变性的模型中研究从神经元损伤到小胶质细胞激活的信号通路。我们建议描述将小胶质细胞吸引到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。我们将利用组织型纤溶酶原激活剂(TPA)，这是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伙伴Annin A2的相互作用来介导小胶质细胞的激活。我们还将分析tPA/Annexin A2依赖的小胶质细胞激活和血脑屏障受损后的效应通路。最后，我们将使用小胶质细胞没有功能的动物，以及在小胶质细胞中表达EGFP的小鼠和双光子显微镜来研究小胶质细胞在中枢神经系统正常的、非病理功能中的作用。 优秀的提案将研究信号，确定小胶质细胞在兴奋性毒性后是神经保护还是神经毒性。该提案的优点包括调查员在前一个供资周期内的生产力。这项研究的发现可能会对小胶质细胞和炎性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.