Ras Proteins in Nerve Tumorigensis

神经肿瘤发生中的 Ras 蛋白

• 批准号: 8667635
• 负责人: NANCY RATNER
• 金额: $ 38.16万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 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/8667635
• 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; 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; public health relevance; ras Proteins; sarcoma; self-renewal; therapy resistant; tumor; tumor growth; tumorigenesis

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，其在 GTP 结合状态下控制细胞内信号传导级联。 Ras 信号传导被 ​​GTP 酶激活蛋白 (GAP)（包括肿瘤抑制因子 NF1）失活。 NF1 功能丧失突变最近被认为与神经母细胞瘤、脑瘤、肺瘤、甲状腺瘤和其他肿瘤类型有关，并与治疗耐药有关。此外，遗传性 NF1 突变会导致 1 型神经纤维瘤病，在这种疾病中，患者会出现无法治愈的良性周围神经鞘雪旺细胞瘤，称为神经纤维瘤。 NF1 患者还容易患侵袭性肉瘤 MPNST，这是 NF1 患者死亡的主要原因。该应用程序的目标有两个。我们将利用 NF1 功能丧失来描绘神经纤维瘤细胞中 Ras 特异性通路。这是因为 NF1 是所有 Ras 蛋白的 GAP：H-、N-、K-、M-、R-Ras 和 RRas2/TC21，并且可能具有其他非 Ras 功能。当 NF1 完全丧失时，所有 Ras 蛋白都会被激活，因此 NF1 模型提供了一个独特的机会来研究单个 Ras 蛋白对体内肿瘤发生的贡献。在目标 1 中，我们将测试在由 NF1 功能丧失（单独或与 RRas2 丧失相结合）驱动的小鼠模型中，H-Ras 的丧失是否会特异性延迟或阻止神经纤维瘤的形成。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，我们将使用新的 Nf1 突变等位基因测试 Ras 激活是否足以形成神经纤维瘤，并使用专门的施万细胞系统来定义 NF1 突变细胞中的 Ras 特异性效应。在目标 3 中，我们将验证我们最先进的外显子组测序，以识别雪旺细胞中 Ras 相关信号通路突变，这些突变与 NF1 功能丧失共同促进 NF1 肿瘤发生。这些研究将共同​​确定 Ras 亚型在癌细胞中的特定功能，并阐明驱动神经纤维瘤形成的分子信号。