Collaborating Mutations in Medulloblastoma

髓母细胞瘤中的协同突变

基本信息

批准号：
8243629
负责人：
MARTINE F. ROUSSEL (SHERR)
金额：
$ 32.06万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8243629
关键词：
Affect Anaplastic Cell Brain CDK6-associated protein p18 CDKN2C gene Cell Cycle Cerebellum Child Cyclin D1 Defect Development Disease Down-Regulation Engineering Erinaceidae Fostering Frequencies Gene Dosage Gene Expression Gene Mutation Genes Genetic Human Lead Maintenance Malignant Neoplasms Malignant neoplasm of brain Methods MicroRNAs Mitogens Molecular Molecular Profiling Mouse Strains Mus Mutation Neoplasms Neurocognitive Neuronal Differentiation Operative Surgical Procedures Other Genetics Patients Pediatric Neoplasm Protein p53 Proteins RNA Radiation therapy Resistance Role Signal Pathway Signal Transduction Stem cells Tumor Suppressor Proteins Work bone morphogenic protein chemotherapy improved kinase inhibitor loss of function medulloblastoma mouse model novel smoothened signaling pathway transcription factor tumor

项目摘要

Medulloblastoma (MB) is the most common malignant brain tumor in children. MB is thought to arise from progenitor cells in the developing cerebellum that fail to exit the cell division cycle properly, thus providing fertile ground for tumor formation. Many genetic anomalies have been identified in human MB, but only a few have been revealed to be causative. We have genetically engineered two different MB-prone mouse strains that lack the cyclin-D-dependent kinase inhibitor, p18lnk4c, a cell cycle regulatory and tumor suppressor protein whose expression was also revealed to be reduced or absent in human MBs. In Specific Aim 1, we propose to document the frequency of inactivation of INK4C/CDKN2C in human MBs and to correlate its loss-of-function with other genetic mutations, gene copy number alterations, and gene expression profiles that define different human MB subsets. We will also explore the combined roles of the C-MYC oncoprotein and p53 tumor suppressor in generating a mouse model of large cell anaplastic MBs, the most aggressive and treatment-resistant form of the disease. Many mouse MBs are characterized by mutations affecting a signaling pathway dominated by the mitogen, Sonic Hedgehog (Shh); genetic alterations affecting the Shh signaling pathway have similarly been documented in a subset of human MBs. Our work has established a role for the bone morphogenic proteins (BMPs) in countering Shh signaling, thereby inhibiting proliferation of mouse MBs, and fostering their neuronal differentiation. Not only do BMPs strongly antagonize MB formation in our mouse models, but downregulation of many BMP-responsive genes is a hallmark of Shh-driven human tumors. In Specific Aim 2, we will study Mathl, a key transcription factor regulated by BMP signaling in an'effort to discern how the activity of this protein is governed, what genes it regulates, and why its role is seemingly essential for MB development. Finally, it is now widely appreciated that small regulatory RNA species (micro-RNAs) globally regulate gene expression and thereby contribute to many forms of cancer. In Specific Aim 3, we propose methods to characterize in detail the micro-RNAs that contribute to MB formation and tumor maintenance in both mice and humans.

髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤。 MB被认为是由发育中的小脑中未能正确退出细胞分裂周期的祖细胞，从而提供肿瘤形成肥沃的地面。在人类MB中已经发现了许多遗传异常，但只有一个很少有人揭示出是病因。我们有基因工程的两种不同的MB易于鼠标缺乏细胞周期蛋白D依赖性激酶抑制剂P18LNK4C的菌株，细胞周期和肿瘤抑制蛋白的表达也被发现在人MB中降低或不存在。具体 AIM 1，我们建议记录INK4C/CDKN2C在人类MB中的灭活频率和将其功能丧失与其他遗传突变，基因拷贝数改变和基因相关联表达曲线定义了不同的人类MB子集。我们还将探讨 C-myc癌蛋白和p53肿瘤抑制剂在产生大细胞播种MBS的小鼠模型中该疾病的最具侵略性和防治形式。许多鼠标MB的特征是影响有丝分裂原位的信号通路的突变，声音刺猬（SHH）；遗传在人类MBS的一部分中，类似地记录了影响SHH信号通路的变化。我们的工作已经确定了骨形态蛋白（BMP）在反对SHH信号传导中的作用，从而抑制小鼠MB的增殖，并促进其神经元分化。不仅是BMP 在我们的小鼠模型中强烈拮抗MB的形成，但是许多BMP响应基因的下调是SHH驱动的人类肿瘤的标志。在特定的目标2中，我们将研究Mathl，一个关键的转录因子由An'fort中的BMP信号调节，以识别该蛋白的活性如何控制的基因调节以及为什么其作用对于MB开发至关重要。最后，现在得到了广泛的赞赏全球小的调节RNA物种（微RNA）调节基因表达，从而有助于多种形式的癌症。在特定目标3中，我们提出了详细表征的方法在小鼠和人类中有助于MB形成和肿瘤维持。