BDNF INDUCED DRUG RESISTANCE IN NEUROBLASTOMA

BDNF 诱导神经母细胞瘤耐药

• 批准号: 2895620
• 负责人: DAVID S MIDDLEMAS
• 金额: $ 10.42万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895620
• 关键词: apoptosis; biological signal transduction; cis platinum compound; cyclophosphamide; cytotoxicity; doxorubicin; drug resistance; enzyme inhibitors; etoposide; growth factor receptors; laboratory mouse; necrosis; neoplasm /cancer pharmacology; neoplastic cell; neuroblastoma; neurotrophic factors; phosphatidylinositol 3 kinase; phospholipase C; phosphorylation; receptor binding; receptor expression; retinoate; site directed mutagenesis; tissue /cell culture; vincristine

DESCRIPTION: There is increasing evidence that growth factors may have multiple effects. In addition to stimulating mitogenesis, growth factors may promote differentiation or act as survival factors during development, or as survival factors to cells undergoing stress due to changed in trophic support or damage due to anticancer drug treatments. In neuroblastoma (NB) expression of TRK, the receptor for nerve growth factor (NGF), has been correlated with a good prognosis. In contrast, data presented in this application demonstrates that expression of TRKB, the receptor for BDNF, is associated with resistance to cisplatin. This application proposes to test the hypothesis that brain derived growth factor (BDNF), which is a ligand for TRKB, induces resistance to cisplatin in a human neuroblastoma (NB) cell line and that this resistance is mediated through one of three potential pathways. Three specific aims have been presented. Specific Aim 1 proposes to determine whether NGF or BDNF protect NB cells from cytotoxic drugs or serum withdrawal. This specific aim will also test compounds etoposide, vincristine, cyclophosphamide and doxorubicin. It will also test whether these compounds cause cell death by apoptosis or necrosis. Additional cell lines will also be tested for these receptors and ligands to determine how relevant these findings are to NB. Specific Aim 2 will define the signaling pathways involved in TRK and TRKB mediated protection of cells from either cytotoxic agents or serum starvation. Three potential pathways of signal transduction have been proposed to investigate: 1) RAS, phosphatidyl inositol-3 kinase, 2) P13K pathway, and 3) phospholipase C-g1(PLC-g1). They also propose to use site specific mutagenesis of the tyrosines in the kinase domain of TRKB which form the binding site for the SHC, P13K or PLC-g1. Additional studies will include specific inhibitors of the TRK and TRKB ,P13K, RAS and PLC-g1, and dominant negative constructs against RAS. In Specific Aim 3 they propose to determine if TRKB or TRK increases drug resistance in vivo using mouse xenograft models.

描述：越来越多的证据表明，增长因素可能会 多重效果。除了刺激有丝分裂，生长因子 可能在发育过程中促进分化或作为生存因素， 或作为因营养变化而承受压力的细胞的生存因素 因抗癌药物治疗而造成的支持或损害。神经母细胞瘤(NB) 神经生长因子(NGF)受体TRK的表达已被 与预后良好相关。相比之下，本报告中提供的数据 应用表明，BDNF受体TrkB的表达是 与顺铂耐药有关。此应用程序建议测试 假设脑源性生长因子(BDNF)是一种配体 对于TrkB，诱导人神经母细胞瘤(NB)细胞对顺铂的耐药性 并且这种抗性是通过以下三种可能的方式之一来调节的 小路。提出了三个具体目标。具体目标1提出 为了确定NGF或BDNF是否保护NB细胞免受细胞毒药物或 停用血清。这个特定的目标还将测试化合物依托泊苷， 长春新碱、环磷酰胺和阿霉素。它还将测试是否 这些化合物通过细胞凋亡或坏死导致细胞死亡。附加单元格 还将对这些细胞株进行这些受体和配体的测试，以确定如何 这些发现与NB有关。具体目标2将定义信令 参与TRK和TrkB介导的细胞保护的通路 细胞毒剂或血清饥饿。三条潜在的信号通路 转导已被提出用于研究：1)RAS，磷脂酰基 2)P13K途径；3)磷脂酶C-G1(PLC-G1)。他们 我还建议使用酶中酪氨酸的定点突变。 TrkB的结构域，形成SHC、P13K或PLC-G1的结合位点。 其他研究将包括TRK和TrkB的特定抑制剂 、P13K、RAS和PLC-G1，以及针对RAS的显性负向结构。在……里面 具体目标3他们建议确定TrkB或TRK是否会增加药物 用小鼠异种移植模型进行体内耐药。