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

 描述（由申请人提供）：我们的研究中心是脑肿瘤的生物学和PID 1的作用，我们最近报道PID 1是神经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性恶性脑肿瘤。我们发现，PID 1过表达在GBM细胞系中具有生长抑制作用，并且较高的PID 1 mRNA水平与较长的患者总生存期相关。在这里，我们将研究PID 1作为GBM治疗增敏剂的作用，并研究其分子机制。PID 1是2006年发现的含有磷酸酪氨酸结合（PTB）结构域的蛋白质。PID 1通过抑制胰岛素信号传导在肥胖介导的胰岛素抵抗中起作用，与阿尔茨海默病有关，并且如我们所示，通过未知机制在神经胶质瘤和成神经管细胞瘤脑肿瘤中具有肿瘤抑制作用。正在进行的实验发现，PID 1使胶质瘤细胞对化疗敏感，并且它是GBM中具有关键作用的受体的新型结合伴侣。在本探索性R21提案中，我们旨在了解PID 1使GBM对化疗敏感并抑制GBM生长的机制。我们的目标是：1）确定PID 1与受体相互作用的机制和特征，以及对信号传导和增殖的影响， 体外和体内研究GBM对化疗药物的增敏作用。我们最近的工作强调了PID 1在脑肿瘤中的重要性，指出了一种潜在的抑制性基因， 和/或PID 1的治疗敏感作用。我们的机制发现的意义可能会扩展到其他疾病，因为PID 1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发现PID 1作为GBM对化疗的敏化剂以及我们将揭示的新机制。这些结果将为设计使GBM对治疗敏感的方式提供基础。

 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.