Ras Proteins in NF1

NF1 中的 Ras 蛋白

基本信息

批准号：
7579293
负责人：
NANCY RATNER
金额：
$ 16.83万
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/7579293
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 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 Role Schwann Cells Signal Pathway Signal Transduction Source Tertiary Protein Structure Testing Xenograft Model cell motility human RRAS2 protein 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型神经纤维瘤病患者（NF1）患有良性周围神经鞘肿瘤称为神经斑。在神经纤维瘤中，在肿瘤schwann细胞中发现了NF1基因中的双重突变，表明肿瘤发生需要在肿瘤雪旺细胞中NF1的功能完全丧失。恶性神经纤维瘤向恶性周围神经鞘肿瘤的进展发生在大约10％的NF1中患者。目前尚无针对神经纤维瘤或MPNST的疗法。 NF1蛋白神经纤维蛋白是一个 RAS蛋白的GTPase激活蛋白（GAP），分子开关，以控制多个信号传导级联。神经纤维蛋白的丧失会导致Schwann细胞中Ras-GTP水平升高。我们在体外使用 NF1中Schwann细胞肿瘤发生的模型系统，以阐明信号通路的基础肿瘤发生。令人惊讶的是，我们发现NF1突变体中迁移和cAMP的积累增加 Schwann细胞没有由HA-RAS-GTP解释。相反，这些表型可能需要相关很少研究RAS蛋白TC21/R-RAS2。 TC21使用下游效应子与其他RAS不同蛋白质。我们建议批判性地评估TC21与神经纤维瘤和MPNST的形成的相关性。具体而言，在目标1和2中，我们将定义TC21在NF1突变体Schwann细胞中的细胞和分子效应，和人类MPNST异种移植物。在AIM 3中，我们将使用鼠标模型来测试TC21延迟或块神经纤维瘤或mpnst构成在一起，预计这些研究将鉴定出新的干预点治疗人NF1疾病。