NEUROTROPHIN RECEPTOR INTERACTIONS

描述：该提案有两大目标。第一个目标是 阐明神经营养因子与trk和trk相互作用的机制 75 kDa神经营养因子受体(P75NTR)传递逆行轴突信号至 神经元胞体。第二个目标是描述信号的特征 P75NTR调节细胞迁移和细胞的信号转导途径 死亡。为了检验NGF诱导血管内化的假设 NGF/TrkA复合体位于轴突末端，并运输这个内体 复合体回到神经元胞体导致MAP的激活 激酶途径等信号通路，轴突转运的各种 将研究NGF信号转导途径的组成部分，其中 胚胎背根神经节感觉神经元的分区培养 (Campenot Chambers)。 神经分化的小鼠P19胚胎癌细胞、胚胎干细胞 细胞和PC12细胞将被用来检验假设 神经营养因子/p75NTR促进神经元和其他细胞的凋亡性死亡 类型，并确定核因子-KB信号通路是否参与 这项规定。此外，为了检验一个主要的 P75NTR的功能配体有待发现，可溶的 将p75NTR的胞外结构域作为亲和探针提取 来自组织提取物的配体，以在组织切片中定位配体，以及 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.