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Ras Proteins in Nerve Tumorigensis

神经肿瘤发生中的 Ras 蛋白

基本信息

批准号：
8804962
负责人：
NANCY RATNER
金额：
$ 39万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804962
关键词：
Accounting Affect Alleles Automobile Driving Benign Brain Brain Neoplasms Cause of Death Cell Proliferation Cell model Cells Common Neoplasm Cytokine Signaling Data Defect Development Differentiation and Growth Disease Fibroblasts GTP Binding GTPase-Activating Proteins Gene Mutation Genes Genetic Genetic Models Goals Guanosine Triphosphate HRAS gene Health Hematopoietic Human Immigration In Vitro Individual Inherited Intervention Knock-in Mouse Lung MEKs Mediating Missense Mutation Modeling Molecular Mus Mutation NF1 gene NF1 tumor suppressor Nerve Neurilemma Neuroblastoma Neurofibromatosis 1 Neurofibromatosis Type 1 Protein Pathogenesis Pathway interactions Patients Peripheral Nerve Sheath Peripheral Nerves Phenotype Pheochromocytoma Point Mutation Protein Isoforms Proteins Proto-Oncogene Proteins c-akt RRAS2 gene Recruitment Activity Role Schwann Cells Signal Pathway Signal Transduction Sorting - Cell Movement Spinal Ganglia Survival Analysis System Tamoxifen Testing Thyroid Gland Work autocrine c-Ha-ras p21 cancer cell cytokine exome sequencing in vivo loss of function loss of function mutation migration mouse model mutant neurofibroma novel ras Proteins sarcoma self-renewal therapy resistant tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Ras proteins are molecular switches that in their GTP-bound state control intracellular signaling cascades. Ras signaling is inactivated by GTPase-activating proteins (GAPs), including the tumor suppressor NF1. NF1 loss of function mutations have recently been implicated in driving neuroblastoma, brain, lung, thyroid and other tumor types and implicated in resistance to therapy. In addition, inherited NF1 mutations result in Neurofibromatosis type 1, a disease in which patients develop incurable benign peripheral nerve sheath Schwann cell tumors called neurofibromas. NF1 patients are also predisposed to aggressive sarcomas, MPNST, which are a leading cause of death in NF1 patients. The goals of this application are two-fold. We shall use NF1 loss of function to delineate Ras-specific pathways in neurofibroma cells. This is because NF1 is a GAP for all Ras proteins: H-, N-, K-, M-, R-Ras and RRas2/TC21, and may have additional, non-Ras, functions. When there is complete loss of NF1, all Ras proteins are activated, so that NF1 models provide a unique opportunity to study the contributions of individual Ras proteins to tumorigenesis in vivo. In Aim 1 we will test whether loss of H-Ras specifically delays or blocks neurofibroma formation in mouse models driven by NF1 loss of function, alone or in combination with RRas2 loss. We will also determine if H-Ras activation is sufficient to promote neurofibroma formation. In Aim 2 we will test if Ras activation is sufficient for neurofibroma formation, using a new Nf1 mutant allele and use specialized Schwann cell systems to define Ras-specific effects in NF1 mutant cells. In Aim 3 we will validate our state-of-the-art exome sequencing to identify Ras-related signaling pathway mutations in Schwann cells that co-operate with NF1 loss of function to promote NF1 tumorigenesis. Together these studies will define Ras isoform specific functions in cancer cells, and clarify molecular signals that drive neurofibroma formation.

描述（由申请人提供）：Ras蛋白是分子开关，在其GP结合状态下控制细胞内信号级联。Ras信号转导被GTP酶激活蛋白（GAP）灭活，包括肿瘤抑制因子NF 1。NF 1功能缺失突变最近被认为与神经母细胞瘤、脑、肺、甲状腺和其他肿瘤类型有关，并与治疗抵抗有关。此外，遗传性NF 1突变导致1型神经纤维瘤病，这是一种患者发展为不可治愈的良性外周神经鞘雪旺细胞瘤（称为神经纤维瘤）的疾病。NF 1患者也易患侵袭性肉瘤MPNST，这是NF 1患者死亡的主要原因。这个应用程序的目标是双重的。我们将使用NF 1功能的丧失来描绘神经纤维瘤细胞中Ras特异性通路。这是因为NF 1是所有Ras蛋白的GAP：H-，N-，K-，M-，R-Ras和RRas 2/TC 21，并且可能具有额外的非Ras功能。当NF 1完全丧失时，所有Ras蛋白都被激活，因此NF 1模型为研究单个Ras蛋白对体内肿瘤发生的贡献提供了独特的机会。在目标1中，我们将测试H-Ras的缺失是否特异性地延迟或阻断由NF 1功能缺失单独或与RRas 2缺失组合驱动的小鼠模型中的神经纤维瘤形成。我们还将确定H-Ras激活是否足以促进神经纤维瘤形成。在目标2中，我们将测试Ras激活是否足以形成神经纤维瘤，使用新的Nf 1突变等位基因，并使用专门的雪旺细胞系统来定义Ras在NF 1突变细胞中的特异性作用。在目标3中，我们将验证我们最先进的外显子组测序，以确定与NF 1功能丧失合作促进NF 1肿瘤发生的许旺细胞中Ras相关信号通路突变。这些研究将共同定义Ras亚型在癌细胞中的特异性功能，并阐明驱动神经纤维瘤形成的分子信号。