NEUROTROPHIN AND TRK EXPRESSION IN CENTRAL NERVOUS SYSTEM PNET

中枢神经系统 PNET 中的神经营养因子和 TRK 表达

• 批准号: 6243866
• 负责人: JOHN TROJANOWSKI
• 金额: $ 19.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243866
• 关键词: biological signal transduction; central nervous system neoplasms; growth factor receptors; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rabbit; medulloblastoma; molecular oncology; neurotrophic factors; pediatric neoplasm /cancer; polymerase chain reaction; receptor expression

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.

该项目追求细胞生物学的最新进展， 髓母细胞瘤（MB）和相关中枢神经系统（CNS） 原始神经外胚层肿瘤（PNTs）通过研究神经营养因子 及其同源受体（trkA、trkB或trkC）， 神经营养因子在这些常见的 小儿脑肿瘤。 MB细胞类似于未成熟的CNS神经元， 他们的祖先，和MB主要发生在第一个十年， 当异位未成熟神经元和/或神经外胚层 祖细胞在小脑中最丰富，其中大多数MB 起来。 可能调节中枢神经系统的相关神经营养因子 神经外胚层祖细胞以及MB和PNT的行为 是神经生长因子（NGF）和相关的神经营养因子，即 脑源性神经营养因子（BDNF）、NT 3和NT 4/5。 这些 因子结合低亲和力NGF受体（LNGFR），但 神经生长因子、脑源性神经营养因子NT 3和NT 4/5的作用被认为是通过 主要通过高亲和力受体，即。trkA（NGF，NT 4/5）， trkB（BDNF，NT 4/5）或trkC（NT 3）。我们实验室的研究 表明Trk受体蛋白在细胞中表达， 发育和成熟的人类小脑，以及MB，PNTB和 由此衍生的细胞系表达Trk蛋白。 因此我们 假设肌萎缩症是由神经外胚层功能障碍引起 祖细胞对内源性神经营养因子的反应。 而不是 经历正常的细胞死亡或完成正常的程序， 神经元分化，这些祖细胞可能会持续在 不成熟的出生后大脑和持续的基因突变， 在MB和相关的PNIPs中。 因此，本项目将 通过鉴定神经营养因子 受体/神经营养因子信号通路可能参与 人类MB的出现和发展以及相关的PNTs CNS。