Ras Proteins in NF1

NF1 中的 Ras 蛋白

基本信息

批准号：
8305041
负责人：
NANCY RATNER
金额：
$ 31.6万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8305041
关键词：
Accounting Alleles Axon Benign Biochemical Biological Assay Biological Models Brain Neoplasms Cell Communication Cell Proliferation Cells Collaborations Cyclic AMP Data Development Disease Dominant-Negative Mutation Eels Embryo Family GTPase-Activating Proteins Gene Targeting Genes Genetic Genetic Transcription Growth Factor Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases HRAS gene Hand Human In Vitro Intervention Kinetics Laboratories Malignant - descriptor Malignant Neoplasms Malignant Peripheral Nerve Sheath Tumor Measures Mediating Messenger RNA Missense Mutation Molecular Morbidity - disease rate Mus Mutant Strains Mice Mutate Mutation NF1 gene Neoplasm Metastasis Nerve Neurofibromatoses Neurofibromatosis 1 Neurofibromatosis Type 1 Protein Partner in relationship Pathogenesis Pathway interactions Patients Peripheral Nerve Sheath Neoplasm Pharmaceutical Preparations Phenotype Proteins R-ras protein RRAS2 gene Research Role Schwann Cells Signal Pathway Signal Transduction Source Tertiary Protein Structure Testing Xenograft Model c-Ha-ras p21 cell motility cell transformation in vitro Model in vivo loss of function migration mouse model mutant neoplastic cell neurofibroma novel novel therapeutics ras Proteins response rho sarcoma small hairpin RNA tumor tumor xenograft tumorigenesis

项目摘要

Patients with neurofibromatosis type 1 (NF1) develop benign peripheral nerve sheath tumors called neurotlbromas. Within neurofibromas, biallelic mutations in the NF1 gene are found in tumor Schwann cells, indicating that tumorigenesis requires complete loss of function at NF1 in tumor Schwann cells. Malignant progression of neurofibromas to malignant peripheral nerve sheath tumors occurs in about 10% of NF1 patients. No therapies currently exist for neurofibroma or MPNST. The NF1 protein, neurofibromin, is a GTPase-activating protein (GAP) for Ras proteins, molecular switches that control multiple signaling cascades. Loss of neurofibromin leads to increased levels of Ras-GTP in Schwann cells. We used in vitro model systems for Schwann cell tumorigenesis in NF1 to clarify signaling pathways underlying tumorigenesis. Surprisingly, we found that increased migration and cAMP accumulation in Nf1 mutant Schwann cells was not accounted for by Ha-Ras-GTP. Rather, these phenotypes may require the related and little studied Ras protein TC21/R-Ras2. TC21 uses downstream effectors differently from other Ras proteins. We propose to critically evaluate the relevance of TC21 to formation of neurofibroma and MPNST. Specifically, in Aims 1 & 2 we will define cellular and molecular effects of TC21 in Nf1 mutant Schwann cells, and human MPNST xenografts. In Aim 3 we will use mouse models to test whether loss of TC21 delays or blocks neurofibroma or MPNST formation Together these studies are anticipated to identify novel intervention points at which to treat human NF1 disease.

1 型神经纤维瘤病 (NF1) 患者会出现良性周围神经鞘肿瘤，称为神经纤维瘤。在神经纤维瘤中，在肿瘤雪旺细胞中发现了 NF1 基因的双等位基因突变，表明肿瘤发生需要肿瘤雪旺细胞中 NF1 功能完全丧失。恶性约 10% 的 NF1 患者会出现神经纤维瘤进展为恶性周围神经鞘瘤的情况患者。目前尚无神经纤维瘤或 MPNST 的治疗方法。 NF1 蛋白，即神经纤维蛋白，是一种 Ras 蛋白的 GTP 酶激活蛋白 (GAP)，控制多种信号传导的分子开关级联。神经纤维蛋白的缺失导致雪旺细胞中 Ras-GTP 水平升高。我们在体外使用 NF1 中雪旺细胞肿瘤发生的模型系统，以阐明潜在的信号通路肿瘤发生。令人惊讶的是，我们发现 Nf1 突变体中的迁移和 cAMP 积累增加 Ha-Ras-GTP 不能解释雪旺细胞。相反，这些表型可能需要相关的 Ras蛋白TC21/R-Ras2研究较少。 TC21 使用下游效应器与其他 Ras 不同蛋白质。我们建议严格评估 TC21 与神经纤维瘤和 MPNST 形成的相关性。具体来说，在目标 1 和 2 中，我们将定义 TC21 在 Nf1 突变雪旺细胞中的细胞和分子效应，和人类 MPNST 异种移植物。在目标 3 中，我们将使用小鼠模型来测试 TC21 延迟丢失或阻断神经纤维瘤或 MPNST 形成这些研究预计将确定新的治疗人类 NF1 疾病的干预点。