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Identification of novel pathways causing NF1-driven Schwann cell tumors

鉴定导致 NF1 驱动的雪旺细胞肿瘤的新途径

基本信息

批准号：
10531621
负责人：
NANCY RATNER
金额：
$ 50.06万
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：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531621
关键词：
Affect Agonist Alleles Arginine Binding Biochemical Biochemistry Biotinylation Cancer Model Cell Proliferation Cell Survival Cells Cessation of life Characteristics Complex Data Development Disease Family Fingers Genetic Genetic Diseases Goals Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Heritability Histology Homeostasis Immunohistochemistry In Vitro Individual KRAS2 gene Location Magnetic Resonance Imaging Mammals Maps Mediating Metabolic Methods Modeling Molecular Biology Techniques Molecular Chaperones Monomeric GTP-Binding Proteins Mus NF1 gene Nervous System Neoplasms Neurofibromatosis 1 Oncogenic Oral Pathway interactions Patients Peripheral Nerves Peroxidases Phosphorylation Phosphorylation Site Preclinical Testing Predisposition Proliferating Property Prostatic Neoplasms Proteins Reagent Role Schwann Cells Signal Pathway Signal Transduction Survival Analysis Syndrome Tamoxifen Technology Testing Therapeutic Time Tumor Suppressor Proteins Western Blotting cell type gain of function immunocytochemistry in vivo inhibitor interdisciplinary approach loss of function member mouse genetics mouse model mutant neoplastic cell neurofibroma novel paralogous gene pharmacologic prostratin protein complex ras Proteins response self-renewal sensor sermons targeted treatment therapeutic target tumor tumorigenesis

项目摘要

Abstract The NF1 gene product, neurofibromin, was identified in 1990, yet fundamental questions remain unanswered concerning its intracellular location(s), binding partners, and signaling properties. It is known that the large (>200kd) tumor suppressor protein contains a small domain that turns of RAS proteins, so that loss of NF1 function leads to RAS activation on cell stimulation. The remaining NF1 sequence can interact with a chaperone, SPRED1, and other proteins in vitro and/or in specific cell types. In Schwan cells, NF1 loss results in formation of neurofibromas, tumors in the peripheral nerves. It is still unknown which interaction partners and RAS proteins are relevant in Schwann cells. Here we propose to identify NF1 interaction partners, including relevant RAS proteins, that contribute to Schwann cell tumorigenesis. This is because in mammals there are six highly homologous NF1-related RAS paralogs, divided into two families. Our studies rely on interdisciplinary approaches, including cell/mouse genetics, and state of the art biochemical and molecular biology techniques, and our expertise in preclinical testing. Our preliminary data, enabled by new reagents and technologies, supports key roles for canonical RAS proteins in NF1 mutant Schwann cell proliferation. We will now assess the specific roles of RAS proteins in primary Schwann cells in vitro, and in neurofibroma in vivo, and test a potential targeted therapy in vivo. Importantly, whether neurofibromin has Schwann cell-specific interaction partners beyond RAS proteins is unknown. Using proximity biotinylation our preliminary studies identify novel potential NF1-interaction partners in Schwann cells. We will identify complexes containing neurofibromin and these proteins and specific RAS paralogs, and additional complexes that may form on cell stimulation, and test if blocking identified pathways is useful therapeutically.

摘要 NF 1基因产物神经纤维蛋白在1990年被发现，但基本问题是，关于它的细胞内定位、结合伴侣和信号传导，特性.已知大的（> 200 kd）肿瘤抑制蛋白含有小的 RAS蛋白的一个结构域，因此NF 1功能的丧失导致RAS激活，细胞刺激剩余的NF 1序列可以与伴侣蛋白SPRED 1相互作用，在体外和/或在特定细胞类型中的其它蛋白质。在许旺细胞中，NF 1缺失导致形成神经纤维瘤，周围神经肿瘤。目前尚不清楚，相互作用伴侣和RAS蛋白在许旺细胞中是相关的。在此，我们建议鉴定NF 1相互作用伙伴，包括相关RAS蛋白，有助于雪旺氏细胞肿瘤发生这是因为在哺乳动物中有六个高度同源的NF 1相关的 RAS旁系同源，分为两个家族。我们的研究依赖于跨学科的方法，包括细胞/小鼠遗传学，以及最先进的生物化学和分子生物学技术和我们在临床前测试方面的专业知识。我们的初步数据，由新的试剂和技术，支持NF 1突变体中典型RAS蛋白的关键作用雪旺细胞增殖。我们现在将评估RAS蛋白在原发性肝癌中的具体作用。体外雪旺细胞和体内神经纤维瘤，并测试一种潜在的靶向治疗， vivo.重要的是，神经纤维蛋白是否有雪旺细胞特异性相互作用伙伴，除了RAS蛋白外，其他蛋白都是未知的。使用邻近生物素化，我们的初步研究在雪旺细胞中鉴定新的潜在NF 1相互作用伙伴。我们将识别复合物含有神经纤维蛋白和这些蛋白质以及特定的RAS旁系同源物，以及另外的可能在细胞刺激时形成的复合物，并测试阻断已识别的通路是否有用治疗上