Tumor-Inhibitory Effects of P1D1 in Gliomas

P1D1 在神经胶质瘤中的肿瘤抑制作用

基本信息

批准号：
8329626
负责人：
ANAT ERDREICH-EPSTEIN
金额：
$ 20万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8329626
关键词：
Adipose tissue Apoptosis Astrocytoma Biology Brain Neoplasms Cell Line Cells Child Clinical Data Databases Development Disadvantaged Disease Ectopic Expression Glioblastoma Glioma Goals Growth Health Human Human Cell Line IRS1 gene In Vitro Insulin Knowledge Link Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Mitochondria Molecular Molecular Mechanisms of Action NOD/SCID mouse Obesity Outcome PTB Domain Patients Phosphorylation Phosphotyrosine Primary Brain Neoplasms Progression-Free Survivals Proteins Publishing Radiation Reporting Research Reverse Transcriptase Polymerase Chain Reaction Rhabdoid Tumor Role S Phase Staining method Stains Testing Time Tumor Biology Tumor Cell Line Weight Work cell type clinically significant design effective therapy gene discovery glucose transport improved knowledge base medulloblastoma mutant novel outcome forecast response stem tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): This project focuses on the role of PID1 (Phosphotyrosine Interaction Domain containing 1) in gliomas. PID1 is a phosphotyrosine binding (PTB) domain-containing protein that was discovered in 2006 and which has never been studied in the context of cancer. Ectopic expression of PID1 has opposite effects on proliferation in different cell types. Using microarrays and quantitative RT-PCR, we found that high expression of PID1 correlates with better outcome in two types of brain tumors, gliomas and medulloblastomas. Our in vitro preliminary data further show that ectopic expression of PID1 has growth-inhibitory effects in brain tumor cell lines from three different types of brain tumors: glioblastomas, medulloblastomas, and atypical teratoid rhabdoid tumors (ATRT). We chose to focus this PID1-centered R21 proposal on gliomas since they constitute the most common primary brain tumor in humans and have grim prognosis when malignant. The goal of this proposal is to uncover the molecular mechanisms by which PID1 mediates its inhibitory effect in gliomas. Specifically, we will test the hypothesis that PID1 exerts its inhibitory effect in malignant gliomas in part through its PTB domain. We propose the following two Specific Aims: 1) To determine the critical domain(s) of PID1 that mediate(s) its inhibitory function in GBM cell lines. In this Aim, we will make mutants of known and predicted domains of PID1 and test their ability to decrease proliferation and induce apoptosis. 2) To examine the effect of PID1 expression on growth of intracranial human cell line-derived GBM tumors in NOD-SCID mice. In this Aim, we will use regulated expression of PID1 and examine the effects of PID1 expression on tumor growth, survival, proliferation, and apoptosis. This work is novel and of high impact, as it will further our knowledge on the molecular mechanisms and functions of PID1 in gliomas, forming the first basis of knowledge about PID1 in any brain tumor and any cancer. The clinical correlation we uncovered in our Preliminary Data highlights the relevance and significance of this topic. In addition, our finding of an inhibitory function for PID1 in three different types of brain tumors suggest that PID1 may also be important in other cancers, and possibly in other diseases, potentially expanding the impact of our work.

描述（由申请人提供）：该项目着重于胶质瘤中PID1（含有1个磷酸酪氨酸相互作用域）的作用。 PID1是一种含磷酸酪氨酸结合（PTB）结构域的蛋白质，在2006年发现，在癌症的背景下从未研究过。 PID1的异位表达对不同细胞类型的增殖具有相反的影响。使用微阵列和定量RT-PCR，我们发现PID1的高表达与两种类型的脑肿瘤，胶质瘤和髓母细胞瘤相关。我们的体外初步数据进一步表明，PID1的异位表达在三种不同类型的脑肿瘤的脑肿瘤细胞系中具有生长抑制作用：胶质母细胞瘤，髓母细胞瘤和非典型terainoid盲型肿瘤（ATRT）。我们选择将这种以PID1为中心的R21提案集中在神经胶质瘤上，因为它们构成了人类中最常见的原发性脑肿瘤，并且在恶性肿瘤时具有严峻的预后。该提案的目的是发现PID1介导其在神经胶质瘤中的抑制作用的分子机制。具体而言，我们将检验以下假设：PID1通过其PTB结构域部分地在恶性神经胶质瘤中发挥抑制作用。我们提出以下两个具体目标： 1）确定介导其在GBM细胞系中抑制功能的PID1的临界域。在此目标中，我们将使PID1的已知和预测域的突变体测试它们降低增殖和诱导凋亡的能力。 2）检验PID1表达对NOD-SCID小鼠中颅内人细胞系源性GBM肿瘤生长的影响。在此目标中，我们将使用PID1的调节表达，并检查PID1表达对肿瘤生长，生存，增殖和凋亡的影响。这项工作是新颖的，具有很高的影响力，因为它将进一步了解PID1在神经胶质瘤中的分子机制和功能，从而构成了任何脑肿瘤和任何癌症中关于PID1知识的第一基础。我们在初步数据中发现的临床相关性突出了该主题的相关性和意义。此外，我们发现PID1在三种不同类型的脑肿瘤中对PID1的抑制功能表明，PID1在其他癌症中也可能很重要，可能在其他疾病中很重要，可能会扩大我们工作的影响。