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: 8525836
• 负责人: Preeti Tandon
• 金额: $ 4.92万
• 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/8525836
• 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（由申请人提供）：NF1基因突变导致1型神经纤维瘤病（NF1），一种以形成周围神经系统良性和恶性肿瘤为特征的疾病。神经纤维蛋白是由 NF1 基因编码的蛋白质，具有肿瘤抑制因子的功能，主要是通过抑制经典 Ras（H-Ras、N-Ras 和 K-Ras）和 R-Ras（R-Ras、TC21 和 M-Ras）亚家族的多种小 G 蛋白。虽然 Ras 激活与 NF1 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 过度激活和 NF1 缺失会诱导各种细胞因子的分泌，进而促进肿瘤生长。具体而言，Nf1-/-雪旺细胞分泌 Kit Ligand，刺激肥大细胞迁移，从而促进神经纤维瘤发病机制。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。提出了两个具体目标来检验这一假设：1) 评估 H、N 和 K-Ras 蛋白在介导 Nf1 缺陷神经纤维瘤的存活、增殖和炎症细胞浸润中的作用 和 MPNST。 2) 鉴定抑制 Ras 信号传导并阻止 NF1 缺陷型神经纤维瘤和 MPNST 细胞存活的新化合物。本研究的总体目标是描绘 Ras 蛋白在 NF1 发病机制中的功能，并确定基于抑制特定 Ras 蛋白的新治疗策略。