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）是儿童中最常见的恶性脑肿瘤。 MB被认为产生于发育中的小脑中的祖细胞无法正常退出细胞分裂周期，从而提供为肿瘤的形成提供了肥沃的土壤。在人类 MB 中已发现许多遗传异常，但只有一种很少有人被证实是致病原因。我们对两种不同的MB易感小鼠进行了基因改造缺乏细胞周期蛋白 D 依赖性激酶抑制剂 p18lnk4c（一种细胞周期调节剂和肿瘤）的菌株抑制蛋白的表达也被发现在人类 MB 中减少或缺失。具体来说目标 1，我们建议记录人类 MB 中 INK4C/CDKN2C 失活的频率，并将其功能丧失与其他基因突变、基因拷贝数改变和基因定义不同人类 MB 子集的表达谱。我们还将探讨以下机构的综合作用： C-MYC 癌蛋白和 p53 肿瘤抑制因子在生成大细胞间变性 MB 小鼠模型中的作用，该疾病最具侵袭性和最难治疗的形式。许多小鼠 MB 的特点是影响由有丝分裂原 Sonic Hedgehog (Shh) 主导的信号通路的突变；遗传的影响 Shh 信号通路的改变在人类 MB 的子集中也有类似的记录。我们的工作已经确定了骨形态发生蛋白 (BMP) 在对抗 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。 BMP 不仅可以在我们的小鼠模型中强烈拮抗 MB 形成，但下调许多 BMP 反应基因是 Shh 驱动的人类肿瘤的一个标志。在具体目标 2 中，我们将研究 Mathl，一个关键的转录因子受 BMP 信号传导调节，试图了解该蛋白质的活性是如何被控制的，它的基因是什么监管，以及为什么它的作用似乎对于 MB 开发至关重要。最后，现在受到广泛赞赏小调节RNA种类（micro-RNA）全局调节基因表达，从而有助于多种形式的癌症。在具体目标 3 中，我们提出了详细表征 micro-RNA 的方法，有助于小鼠和人类的MB形成和肿瘤维持。