NEUROTROPHIN AND TRK EXPRESSION IN CENTRAL NERVOUS SYSTEM PNET

该项目追求的是细胞生物学方面的最新进展。 髓母细胞瘤及其相关中枢神经系统 神经营养因子对原始神经外胚层肿瘤的研究 和他们的同源受体(TrkA、TrkB或trkC)来获得洞察力 神经营养因子在这些常见疾病进展中的作用 儿童脑瘤。MB细胞类似于未成熟的CNS神经元或 它们的祖先和抵押贷款证券化主要发生在 异位未成熟神经元和/或神经外胚层的生命 祖细胞在小脑中最丰富，在那里MBS最多 站起来。相关的中枢神经营养因子可能调节 神经外胚层祖细胞以及MBS和PNETs的行为 神经生长因子(NGF)和相关的神经营养因子，即 脑源性神经营养因子、NT3和NT4/5。这些 与低亲和力NGF受体(LNGFR)结合的因子，但 NGF、BDNF、NT3和NT4/5的作用被认为是通过介导的 主要通过高亲和力受体，即。TrkA(NGF，NT4/5)， TrkB(BDNF，NT4/5)或trkC(NT3)。来自我们实验室的研究 表明trk受体蛋白在 发育和成熟的人小脑，MBS、PNETs和 从其衍生的细胞系表达trk蛋白。因此，我们 假设MBS是由神经外胚层衰竭引起的 祖细胞对内源性神经营养因子做出反应。而不是 经历正常的细胞死亡或完成正常的程序 神经分化，这些祖细胞可能会在 未成熟的出生后大脑和维持基因突变导致的 在MBS和相关的PNETs中。因此，该项目将 通过确定神经营养因子来研究这些问题 受体/神经营养因子信号通路可能参与 人类MBS及相关PNETs的发生和发展 中枢神经系统。

This Project pursues recent advances in the cell biology of medulloblastomas (MBs) and related central nervous system (CNS) primitive neuroectodermal tumors (PNETs) by studying neurotrophins and their cognate receptors (trkA, trkB or trkC) to gain insights into the role of neurotrophins in the progression of these common pediatric brain tumors. MB cells resemble immature CNS neurons or their progenitors, and MBs primarily occur in the first decade of life when heterotopic immature neurons and/or neuroectodermal progenitor cells are most abundant in cerebellum where most MBs arise. The relevant CNS neurotrophins that might regulate the behavior of neuroectodermal progenitors as well as MBs and PNETs are nerve growth factor (NGF) and related neurotrophins, i.e. brain derived neurotrophic factor (BDNF), NT3 and NT4/5. These factors bind to the low affinity NGF receptor (LNGFR), but the effects of NGF, BDNF NT3 and NT4/5 are thought to be mediated primarily by high affinity receptors, i.e.. trkA (NGF, NT4/5), trkB (BDNF, NT4/5) or trkC (NT3). Studies from our laboratory indicate that trk receptor proteins are expressed in the developing and mature human cerebellum, and that MBs, PNETs and cell lines derived therefrom express trk proteins. Thus, we hypothesize that MBs arise from the failure of neuroectodermal progenitors to respond to endogenous neurotrophins. Instead of undergoing normal cell death or completing a normal program of neuronal differentiation, these progenitors may persist in the immature postnatal brain and sustain genetic mutations that result in MBs and related PNETs. Accordingly, this Project will investigate these issues by identifying the neurotrophin receptor/neurotrophin signaling pathways that may be involved in the emergence and progression of human MBs and related PNETs of the CNS.