Characterizing the role of specific Ras proteins in neurofibroma and MPNST format

表征特定 Ras 蛋白在神经纤维瘤和 MPNST 格式中的作用

• 批准号: 8775606
• 负责人: Preeti Tandon
• 金额: $ 5.33万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775606
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Affect; Antibodies; Benign; Biochemical; Biological Assay; Cells; Clinical Trials; Collaborations; Cytokine Gene; Data; Development; Disease; Dose; Drug Kinetics; Effectiveness; Evaluation; Gene Expression; Genetic; Genetic Screening; Genotype; Goals; Growth; Growth Factor; HRAS gene; Hematopoietic; Individual; Infiltration; Inflammatory; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Measures; Mediating; Migration Assay; Monitor; Monomeric GTP-Binding Proteins; Mus; Mutation; NF1 gene; Nerve Tissue; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Non-Malignant; Pathogenesis; Patients; Peripheral Nerves; Peripheral Nervous System Malignant Neoplasms; Pharmaceutical Preparations; Play; Property; Protein Family; Protein Isoforms; Proteins; RRAS2 gene; Relative (related person); Research; Role; Schwann Cells; Signal Transduction; Stem Cell Factor; Testing; Therapeutic; Tumor Cell Line; Tumor Suppressor Proteins; Xenograft procedure; base; c-Ha-ras p21; cell motility; cytokine; direct application; effective therapy; efficacy testing; gene function; high throughput screening; human disease; in vivo; insight; loss of function; mast cell; medical schools; mouse model; neoplastic cell; neurofibroma; novel; novel therapeutics; prevent; progenitor; protein expression; public health relevance; ras Proteins; sarcoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; yeast genetics

DESCRIPTION (provided by applicant): Mutations in the NF1 gene cause Neurofibromatosis type 1 (NF1), a disease characterized by the formation of benign and malignant tumors of the peripheral nervous system. Neurofibromin, the protein encoded by the NF1 gene, functions as a tumor suppressor, largely by inhibiting multiple small G-proteins from the classic Ras (H-Ras, N-Ras and K-Ras) and R-Ras (R-Ras, TC21 and M-Ras) subfamilies. While Ras activation has been implicated in the pathogenesis of NF1 associated tumors, the relative contributions of specific classic Ras family proteins to tumorigenesis remain poorly understood. Increasing evidence supports the notion that Ras hyperactivation and NF1 loss induces the secretion of various cytokines, which in turn promote tumor growth. Specifically, Nf1-/- Schwann cells secrete Kit Ligand, which stimulates mast cell migration and thus contributes to neurofibroma pathogenesis. Since the role of tumor microenvironment in NF1 tumorigenesis is becoming increasingly apparent, it is important to understand the mechanisms that alter tumor stroma to facilitate malignant transformation and progression. In order to characterize the role of H-Ras, N-Ras and K-Ras proteins in neurofibroma and MPNST development, we hypothesize that specific Ras proteins play distinct roles in neurofibroma and MPNST formation. Two specific aims are proposed to test this hypothesis: 1) Assess the role of H, N and K-Ras proteins in mediating survival, proliferation and inflammatory cell infiltration in Nf1 deficient neurofibromas and MPNSTs. 2) Identify novel compounds that inhibit Ras signaling and prevent survival of NF1 deficient neurofibroma and MPNST cells.The overall goal of this research is to delineate the functions of Ras proteins in NF1 pathogenesis and to identify novel therapeutic strategies based on inhibition of specific Ras proteins.

描述（申请人提供）：NF 1基因突变导致1型神经纤维瘤病（NF 1），这是一种以周围神经系统良性和恶性肿瘤形成为特征的疾病。神经纤维蛋白是由NF 1基因编码的蛋白质，主要通过抑制来自经典Ras（H-Ras、N-Ras和K-Ras）和R-Ras（R-Ras、TC 21和M-Ras）亚家族的多种小G蛋白而发挥肿瘤抑制剂的作用。虽然Ras激活与NF 1相关肿瘤的发病机制有关，但特定经典Ras家族蛋白对肿瘤发生的相对贡献仍知之甚少。越来越多的证据支持Ras过度活化和NF1丢失诱导各种细胞因子分泌的观点，这些细胞因子反过来促进肿瘤生长。具体而言，Nf1-/-雪旺细胞分泌Kit配体，其刺激肥大细胞迁移，从而有助于神经纤维瘤发病。由于肿瘤微环境在NF1肿瘤发生中的作用越来越明显，因此了解改变肿瘤基质以促进恶性转化和进展的机制非常重要。为了表征H-Ras、N-Ras和K-Ras蛋白在神经纤维瘤和MPNST发展中的作用，我们假设特定的Ras蛋白在神经纤维瘤和MPNST形成中发挥不同的作用。我们提出了两个具体的目标来验证这一假设：1）评估H，N和K-Ras蛋白在Nf1缺陷神经纤维瘤中介导的存活，增殖和炎性细胞浸润中的作用 MPNST。2)本研究的总体目标是阐明Ras蛋白在NF1发病机制中的功能，并确定基于抑制特定Ras蛋白的新的治疗策略。