MECHANISMS OF EPSTEIN BARR VIRUS PERSISTENCE IN B CELLS

描述：（申请人的摘要）在许多神经变性， 已经发现小胶质细胞/巨噬细胞与神经病变相关。 因此，假设小胶质细胞/巨噬细胞可能加剧 神经退行性疾病 一种受体酪氨酸激酶，Mer，表达于 巨噬细胞，最近已显示参与信号转导， 下调免疫反应。 Mer功能突变（Mer kd）小鼠 是通过在细胞质中缺失酪氨酸激酶结构域而产生的 通过基因靶向进行跟踪。 Mer小鼠在LPS攻击后表现出更大的 死亡率，TNF-α水平升高，NF-κ B核 易位，并且与野生型小鼠相比凋亡减少。 因此，我们认为， mer参与了一个信号转导途径， 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CNS中的作用 将研究脱髓鞘。 在功能性敲除小鼠中，使用 遗传和神经毒素诱导的脱髓鞘模型中，Mer的作用将 进行评估。 第二，Mer对TNF-α产生的影响 在巨噬细胞和DCNS中脱髓鞘将在体内和在 体外 最后，将产生Mer转基因小鼠以分析Mer转基因小鼠的基因表达。 Mer过表达对小胶质细胞/巨噬细胞活化和CNS影响 脱髓鞘 这些实验将阐明 小胶质细胞/巨噬细胞在CNS脱髓鞘中的作用，并提供分子靶点 可以用于神经退行性疾病的治疗， 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.