BDNF INDUCED DRUG RESISTANCE IN NEUROBLASTOMA

BDNF 诱导神经母细胞瘤耐药

• 批准号: 2458273
• 负责人: DAVID S MIDDLEMAS
• 金额: $ 9.87万
• 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/2458273
• 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，生长因子可能 多重影响 除了刺激有丝分裂，生长因子 可以促进分化或在发育期间充当存活因子， 或作为细胞的存活因子，其由于营养改变而经受应激 支持或损害由于抗癌药物治疗。 神经母细胞瘤（NB） TRK的表达，神经生长因子（NGF）的受体，已经被证实是神经生长因子的受体。 与良好的预后相关。 相比之下，本报告中提供的数据 应用表明，表达TRKB，BDNF的受体， 与顺铂耐药相关。 本申请旨在测试 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 线，这种阻力是通过三个潜在的介导 途径。 提出了三个具体目标。 具体目标1建议 确定NGF或BDNF是否保护NB细胞免受细胞毒性药物的影响， 血清抽取 这一具体目标也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 这些化合物通过凋亡或坏死引起细胞死亡。 另外的细胞 还将对这些受体和配体进行检测，以确定 这些发现与NB有关。 具体目标2将定义信令 参与TRK和TRKB介导的保护细胞免受 细胞毒剂或血清饥饿。 三种潜在的信号通路 转导已被提议研究：1）RAS，磷脂酰 肌醇-3激酶，2）P13 K途径，和3）磷脂酶C-g1（PLC-g1）。 他们 还建议使用激酶中酪氨酸的位点特异性诱变 TRKB的结构域，其形成SHC、P13 K或PLC-g1的结合位点。 其他研究将包括TRK和TRKB的特异性抑制剂 、P13 K、RAS和PLC-g1，以及针对RAS的显性阴性构建体。 在 具体目标3他们建议确定TRKB或TRK是否增加药物 使用小鼠异种移植物模型进行体内抗性。