MICROGLIA/MACROPHAGES IN CNS DEMYELINATION

描述：(申请人摘要)在一些神经退行性疾病中， 小胶质细胞/巨噬细胞被发现与神经病变相关。 因此，推测小胶质细胞/巨噬细胞可能加重 神经退行性疾病。一种受体酪氨酸激酶，Mer，表达于 巨噬细胞，最近被证明参与信号转导和 免疫反应的下调。Mer功能突变(Mer Kd)小鼠 WEL是由细胞质中的酪氨酸激酶结构域缺失而产生的 通过基因打靶来尾巴。Mer小鼠在内毒素刺激下表现出更大的 肿瘤坏死因子-α水平升高的死亡率增加了核因子-kB核 易位，与野生型小鼠相比，细胞凋亡减少。因此， Mer参与了一条信号转导通路，该通路可以减弱 巨噬细胞通过调节促炎细胞因子和 程序性细胞死亡。在这项提案中，MER在中枢神经系统中的作用 脱髓鞘情况将进行调查。在功能正常的基因敲除鼠标中，使用 遗传和神经毒素诱导的脱髓鞘模型，Mer Will的作用 被评估。第二，Mer对信号转导的肿瘤坏死因子-α产生的影响 在巨噬细胞和DCNS中脱髓鞘作用将在体内和在 体外培养。最后，将产生一只Mer转基因小鼠来分析 Mer过表达对小胶质细胞/巨噬细胞活化及中枢神经系统的影响 脱髓鞘。这些实验将阐明 小胶质细胞/巨噬细胞在中枢神经系统脱髓鞘中的作用及其分子靶点 可用于开发治疗神经退行性变和 脱髓鞘疾病。

DESCRIPTION: (Applicant's abstract) In a number of neurodegenerative, microglia/macrophages have been found associated within the neural lesions. Thus, it is postulated that microglia/macrophages may exacerbate neurodegenerative diseases. A receptor tyrosine kinase, Mer, expressed on macrophage, has recently been shown involved in signal transduction and downregulation of the immune response. Mer functional mutant (Mer kd) mice wer generated by deletion of a tyrosine kinase domain in the cytoplasmic tail by gene targeting. Mer mice upon LPS challenge showed greater mortality, elevated in the levels of TNF-alpha, increase NF- kB nuclear translocation, and decreased apoptosis as compared to wildtype mice. Hence, Mer is involved in a signal transduction pathway that can attenuate macrophages through the regulation of pro-inflammatory cytokines and programmed cell death. In this proposal, the role of Mer in CNS demyelination will be investigated. In a functional knockout mouse, using a genetic and neurotoxin-induced model of demyelination, the role of Mer will be assessed . Secondly, the effect of Mer on signally TNF-alpha production in macrophages and in DCNS demyelination will be elucidate in vivo and in vitro. Finally, a Mer transgenic mouse will be generated to analyze the impact of Mer overexpression on microglia/macrophage activation and CNS demyelination. These experiments will elucidate the role of microglia/macrophages in CNS demyelination and provide a molecular target that can be used in the development of therapies for neurodegenerative and demyelination diseases.