Ras Proteins in Nerve Tumorigensis

描述（由申请人提供）：Ras蛋白是gtp结合状态下控制细胞内信号级联的分子开关。Ras信号被gtpase激活蛋白（gap）灭活，包括肿瘤抑制因子NF1。最近，NF1功能突变丧失与神经母细胞瘤、脑、肺、甲状腺和其他肿瘤类型的驱动有关，并与治疗耐药有关。此外，遗传性NF1突变导致1型神经纤维瘤病，患者发展为不可治愈的良性周围神经鞘雪旺细胞肿瘤，称为神经纤维瘤。NF1患者也易患侵袭性肉瘤，即MPNST，这是NF1患者死亡的主要原因。这个应用程序的目标有两个。我们将使用NF1功能丧失来描述神经纤维瘤细胞中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，并且可能具有额外的非Ras功能。当NF1完全丧失时，所有Ras蛋白都被激活，因此NF1模型提供了一个独特的机会来研究个体Ras蛋白对体内肿瘤发生的贡献。在Aim 1中，我们将测试在NF1功能丧失驱动的小鼠模型中，H-Ras的缺失是否特异性地延迟或阻断神经纤维瘤的形成，单独或联合RRas2缺失。我们还将确定H-Ras激活是否足以促进神经纤维瘤的形成。在目标2中，我们将测试Ras激活是否足以形成神经纤维瘤，使用一个新的Nf1突变等位基因，并使用专门的雪旺细胞系统来定义Ras在Nf1突变细胞中的特异性作用。在Aim 3中，我们将验证我们最先进的外显子组测序，以确定雪旺细胞中与NF1功能丧失合作以促进NF1肿瘤发生的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定功能，并阐明驱动神经纤维瘤形成的分子信号。

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.