NEUROTROPHIN RECEPTOR INTERACTIONS

说明：该提案有两个广泛的目标。 第一个目标是 阐明神经营养因子与trk相互作用的机制， 75 kDa神经营养因子受体（p75 NTR）传递逆行轴突信号， 神经元细胞体。 第二个目标是表征信号 p75 NTR调节细胞迁移和细胞凋亡的转导途径 死亡 为了验证NGF诱导细胞内化的假设， NGF/trkA复合物在轴突末端和运输这种内体 复合物回到神经元细胞体，导致MAP激活 激酶途径和其他信号传导途径，轴突运输的各种 将检查NGF信号转导途径的组分，其中 隔室培养胚胎背根神经节感觉神经元 （Campenot Chambers）. 神经元分化的小鼠P19胚胎癌细胞，胚胎干细胞 细胞（ES）和PC 12细胞将被用来测试假设， 神经营养因子/p75 NTR增强神经元和其它细胞凋亡 类型，并确定NF-κ B信号通路是否参与 这个规定。 此外，为了检验一个主要的假设， p75 NTR的功能配体仍有待发现，可溶性 p75 NTR的胞外域将用作亲和探针以提取 从组织提取的配体，定位组织切片中的配体， 筛选在哺乳动物细胞中表达的cDNA文库。

DESCRIPTION: The proposal has 2 broad goals. The first goal is to elucidate the mechanisms by which neurotrophin interactions with trk and 75kDa neurotrophin receptors (p75NTR) convey retrograde axonal signals to the neuronal cell body. The second goal is to characterize the signal transduction pathways by which p75NTR regulates cell migration and cell death. To test the hypothesis that NGF induces internalization of the NGF/trkA complexes at the axon terminus and transports this endosomal complex back to the neuronal cell body leading to activation of the MAP kinase pathway and other signaling pathways, axonal transport of various components of the NGF signal transduction pathway will be examined in which embryo dorsal root ganglion sensory neurons in compartmentalize cultures (Campenot Chambers). Neuronal differentiated mouse P19 embryonic carcinoma cells, embryonic stem cells (ES) and PC12 cells will be employed to test the hypothesis that neurotrophin/p75NTR enhances apoptotic death of neuronal and other cell types, and to determine whether the NF-KB signaling pathway participate in this regulation. In addition, to test the hypothesis that a major functional ligand of the p75NTR remains to be discovered, the soluble ectodomain of the p75NTR will be used as an affinity probe to extract ligands from tissue extracts, to localize ligands in tissue sections and to screen cDNA libraries expressed in mammalian cells.