Molecular mechanism of PID1, a novel tumor inhibitor, in glioblastomas

新型肿瘤抑制剂PID1在胶质母细胞瘤中的分子机制

• 批准号: 9020123
• 负责人: ANAT ERDREICH-EPSTEIN
• 金额: $ 21.85万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9020123
• 关键词: Abbreviations; Adipocytes; Adult; Alzheimer' s Disease; Amino Acids; Applications Grants; Binding; Biology; Brain; Brain Neoplasms; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chemosensitization; Childhood; Cisplatin; Data; Data Set; Development; Disease; EGF gene; EGFR inhibition; Embryo; Epidermal Growth Factor Receptor; Etoposide; Fibroblasts; Figs - dietary; Future; Glioblastoma; Glioma; Goals; Growth; Health; Human; In Vitro; Insulin; Insulin Resistance; Interleukin-6; Knockout Mice; Knowledge; Lead; Link; Malignant Glioma; Malignant neoplasm of brain; Mediating; Messenger RNA; Mitochondria; Modality; Molecular; Mus; Muscle Cells; Obesity; PTB Domain; Patients; Phosphorylation; Phosphotyrosine; Proteins; Regulation; Reporting; Research; Rhabdoid Tumor; Role; Serum; Signal Transduction; Starvation; Tumor Cell Line; Tumor Suppressor Proteins; Tyrosine Phosphorylation; Work; base; chemotherapy; design; human disease; improved; in vivo; inhibitor/antagonist; innovation; insulin signaling; medulloblastoma; mimetics; mutant; novel; outcome forecast; overexpression; public health relevance; receptor; research study; response; temozolomide; tool; tumor

 DESCRIPTION (provided by applicant): Our research centers on the biology of brain tumors and on the role of PID1, which we recently reported to be a candidate tumor suppressor in gliomas and medulloblastomas. In this exploratory R21 proposal we will focus on glioblastoma (GBM), the most common primary malignant brain tumor in humans. We showed that PID1 overexpression was growth-inhibitory in cell lines from GBM and that higher PID1 mRNA levels were correlated with longer patient overall survival. Here we will examine the role of PID1 as a sensitizer of GBM to therapy and examine its molecular mechanism. PID1 is a phosphotyrosine binding (PTB) domain-containing protein discovered in 2006. PID1 functions in obesity-mediated insulin resistance via inhibition of insulin signaling, is linked to Alzheimer's disease, and as we showed, has tumor-suppressive effects in glioma and medulloblastoma brain tumors by an unknown mechanism. Ongoing experiments find that PID1 sensitizes glioma cells to chemotherapy and that it is a novel binding partner to a receptor with critical roles in GBM. In this Exploratory R21 proposal we aim to understand the mechanism by which PID1 sensitizes GBM to chemotherapy and inhibits GBM growth. Our Aims will 1) determine the mechanism and characteristics of PID1 interactions with the receptor and effect on signaling and proliferation in GBM, and 2) investigate the sensitization of GBM to chemotherapy in vitro and in vivo. Our recent work highlights the significance of PID1 in brain tumors, pointing to a potential inhibitory and/or therapy-sensitizing role of PID1. The significance of our mechanistic findings will likely extend to other diseases, as PID1 is relevant in obesity, insulin resistance, and Alzheimer's disease. The main innovative aspects of this work include the finding of PID1 as a sensitizer of GBM to chemotherapy and the novel mechanism we will uncover. These results will provide the basis to design modalities that will sensitize GBM to therapy.

 描述(申请人提供)：我们的研究集中在脑肿瘤的生物学和PID1的作用，我们最近报道PID1是胶质瘤和髓母细胞瘤的候选肿瘤抑制因子。在这个探索性的R21提案中，我们将重点关注胶质母细胞瘤(GBM)，这是人类最常见的原发恶性脑瘤。我们发现PID1的过度表达对GBM细胞系的生长有抑制作用，并且PID1的高水平与患者总生存期的延长相关。在这里，我们将检测PID1作为GBM的增敏剂对治疗的作用，并探讨其分子机制。PID1是2006年发现的一种含磷酸酪氨酸结合(PTB)结构域的蛋白质。PID1通过抑制胰岛素信号通路在肥胖介导的胰岛素抵抗中发挥作用，与阿尔茨海默病有关，如我们所示，PID1在胶质瘤和髓母细胞瘤脑瘤中具有肿瘤抑制作用，机制不明。正在进行的实验发现，PID1使胶质瘤细胞对化疗敏感，它是一种新的与受体结合的伙伴，在GBM中具有关键作用。在这个探索性的R21方案中，我们的目标是了解PID1使GBM对化疗敏感并抑制GBM生长的机制。我们的目标将1)确定PID1与受体相互作用的机制和特征，以及对信号和增殖的影响 2)体外和体内研究GBM对化疗的增敏作用。我们最近的工作强调了PID1在脑瘤中的重要性，指出了一种潜在的抑制作用 和/或PID1的治疗敏感性作用。我们的机制发现的意义可能会延伸到其他疾病，因为PID1与肥胖、胰岛素抵抗和阿尔茨海默病有关。这项工作的主要创新方面包括PID1作为GBM对化疗的敏感剂的发现以及我们将揭示的新机制。这些结果将为设计使GBM对治疗敏感的模式提供基础。