The Role of PDGFR in Medulloblastoma Progression

PDGFR 在髓母细胞瘤进展中的作用

• 批准号: 7095792
• 负责人: TOBEY J. MACDONALD
• 金额: $ 26.52万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095792
• 关键词: medulloblastoma; neoplasm /cancer; role

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children. To approach the problem of effective therapy, the progression of human medulloblastoma must first be understood. We hypothesize that platelet-derived growth factor (PDGFR)-mediated signal transduction enhances tumor cell responses that promote the growth and metastatic spread of medulloblastoma, and have shown that (i) PDGFR is significantly overexpressed by metastatic medulloblastomas, (ii) inhibitors of medulloblastoma cell PDGFR activity decrease phosphorylation of the downstream signaling target, MAPK, alter gene expression, and decrease cell migration and survival and (iii) in silico analysis of 135 known pro-metastatic genes within independent datasets of microarray gene expression of medulloblastomas, only three genes, including DDGFR, demonstrated detectable mRNA expression in at least one third of all tumors analyzed and significant overexpression by metastatic tumors in each dataset. These data, combined with the preliminary data showing that both alpha (PDGFRA) and beta (PDGFRB) subtypes of the receptor are 1) expressed on the RNA and protein level by medulloblastoma tumors and cells, 2) sparsely expressed by normal brain, 3) activated in an autocrine and paracrine fashion in medulloblastoma cells, and 4) capable of inducing apoptosis of medulloblastoma cells in a dose-dependent manner following treatment with a selective inhibitor of PDGFR tyrosine kinase activity, suggest a mechanism by which PDGFR may be vital for medulloblastoma growth and progression. Thus, PDGFR is a potential novel target for therapeutic intervention. To test this hypothesis we will employ human medulloblastoma cell lines. We will (i) conduct comprehensive in vitro studies to determine the PDGFR signaling cascade and its effects on survival, proliferation, adhesion, migration and invasion, (ii) determine the key gene expression changes induced by PDGFR signaling in these cells, (iii) develop medulloblastoma cells with deficient PDGFR expression by inducible siRNA transfection specific for each PDGFR and determine the effect of inhibited expression and activity on survival, proliferation and migration in vitro and growth and metastasis in vivo, and (iv) determine the expression pattern of phosphorylated PDGFR protein and its correlation with metastasis and outcome in human medulloblastomas as a way to assess the potential clinical utility of PDGFR inhibitors for this disease

描述（由申请人提供）：髓母细胞瘤是儿童最常见的恶性脑肿瘤。为了解决有效治疗的问题，必须首先了解人类髓母细胞瘤的进展。 We hypothesize that platelet-derived growth factor (PDGFR)-mediated signal transduction enhances tumor cell responses that promote the growth and metastatic spread of medulloblastoma, and have shown that (i) PDGFR is significantly overexpressed by metastatic medulloblastomas, (ii) inhibitors of medulloblastoma cell PDGFR activity decrease phosphorylation of the downstream signaling target, MAPK,在对髓母细胞瘤的微阵列基因表达的独立数据集中对135个已知的促次迁移基因的硅分析中的细胞迁移和（iii）的降低，包括DDGFR，包括DDGFR，包括三个基因，包括三个基因，包括DDGFR，在每个肿瘤中通过分析的至少三分之一的肿瘤中的三分之一表现出可检测的mRNA表达，并通过分析了每个数据。这些数据与初步数据相结合，表明受体的α（PDGFRA）和β（pDGFRB）亚型均在RNA和蛋白质水平上表达为1），由髓母细胞瘤肿瘤和细胞在RNA和蛋白质水平上表达，2）由髓样细胞稀疏地表达，正常大脑表达，3）在自动蛋白和甲状腺旁的小细胞中激活，并在Medapline spapline castosy中激活，并在Medaplarine spapline sistion中，并在Medlastosy sistive中，以及4种脑中的脑料症，并在4个）中，并在4个。用PDGFR酪氨酸激酶活性的选择性抑制剂治疗后，髓母细胞瘤细胞以剂量依赖性方式提出了一种机制，通过这种机制，PDGFR对髓母细胞瘤的生长和进展可能至关重要。因此，PDGFR是治疗干预的潜在新靶标。为了检验该假设，我们将采用人类髓母细胞瘤细胞系。我们将（i）（i）进行全面的体外研究，以确定PDGFR信号级联及其对生存，增殖，粘附，迁移和侵袭的影响，（ii）确定这些细胞中PDGFR信号引起的关键基因表达变化，（iii）在髓母细胞中通过介导的pDGFR表达以及对含有的pDGFR表达的缺陷以及对含有的sirna pdgfr的表达以及对明确的sirna Trive the nirna the the the the the the section the the the the the the the the the the the section的表达以及对含有型号PD的表达的影响。在体内生存，增殖和迁移，体内生长和转移，以及（iv）确定磷酸化的PDGFR蛋白的表达模式及其与转移的相关性以及人类髓母细胞瘤中这种疾病的潜在临床抑制剂的潜在临床实用性的方法