Redox Signaling in Neurofibromatosis

神经纤维瘤病中的氧化还原信号传导

• 批准号: 10352387
• 负责人: Maria Clara Franco
• 金额: $ 31.58万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352387
• 关键词: 3-nitrotyrosine; Acoustic Nerve; Acoustic Neuroma; Address; Affect; American; Amino Acids; Antineoplastic Agents; Biological Assay; Brain Neoplasms; Brain Stem; Categories; Cell Proliferation; Cell Survival; Cells; Cerebellum; Child; Complex; Cytoskeleton; Data; Development; Disease; Down-Regulation; Equilibrium; Ethnic Origin; Exhibits; FRAP1 gene; Foundations; Future; GA-binding protein transcription factor; Galectin 1; Gene Mutation; Genes; Genetic; Genetic Code; Genetic Transcription; Glycolysis; Goals; Growth; Heat-Shock Proteins 90; Hereditary Disease; Human; Immunoprecipitation; Inflammatory; Intervention; Leg; Life; Location; MEKs; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medical; Metabolic; Metabolism; Mitochondria; Modality; Modification; Molecular Chaperones; Mutation; Nerve; Nervous System Neoplasms; Nervous system structure; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 2; Neurofibromin 2; Nitrates; Normal tissue morphology; Numbness; Operative Surgical Procedures; Oregon; Oxidants; Oxidation-Reduction; Oxidative Phosphorylation; Oxides; Pathologic; Pathway Analysis; Pathway interactions; Patients; Peroxonitrite; Pharmacological Treatment; Play; Prevention; Process; Protein Kinase; Proteins; Publishing; Quantitative Reverse Transcriptase PCR; Race; Reactive Nitrogen Species; Recombinant Proteins; Regulation; Research; Resources; Respiration; Risk; Role; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Spinal Neoplasms; Testing; Tissues; Tumor Debulking; Tumor Suppressor Proteins; Tyrosine; Universities; Vimentin; Vision; Work; arm; base; complex IV; deafness; drug development; efficacious treatment; gain of function; human disease; innovation; insight; kinase inhibitor; knowledge of results; metabolic phenotype; nerve damage; nervous system disorder; new therapeutic target; nitration; novel; novel therapeutics; oxidation; prevent; protein function; sex; side effect; targeted treatment; therapeutic target; tool; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor metabolism; tumorigenic; young adult

PROJECT SUMMARY Neurofibromatosis type 2 (NF2) is a debilitating and medically-incurable tumor disorder of the nervous system caused by inactivating mutations of the gene that encodes merlin tumor suppressor. NF2 patients develop multiple schwannomas throughout the nervous system for which there is no pharmacological treatment. Patients undergo debilitating repeated invasive surgeries to remove or debulk tumors growing along the nerves, risking permanent nerve damage. Growing evidence implicates protein oxidation by reactive nitrogen species as a major contributor to tumor growth, but the specific oxidative modifications and target proteins that mediate tumorigenic activity are unknown. Our goals are to reveal novel mechanisms that mediate dysregulation of cell proliferation in NF2 and identify specific oxidatively modified proteins that may serve as tumor-directed, non-invasive therapeutic targets for NF2 and other tumors. Our exciting preliminary findings revealed that one such oxidative modification, tyrosine (Tyr) nitration, selectively supports schwannoma cell survival and contributes to schwannoma metabolic phenotype by decreasing oxidative phosphorylation complex IV levels and activity, while increasing glycolysis and glutaminolysis. Further, we identified 31 endogenous nitrated proteins in schwannomas, including Hsp90, which we showed decreases mitochondrial respiration when nitrated, the transcription factor GABP, responsible for the regulation of complex IV expression, and 5 tumorigenic proteins that participate in signaling pathways that are deregulated in NF2. We will thus test the hypothesis that selective Tyr nitration of proteins in NF2 dysregulates mitochondrial respiration and signaling pathways that are responsible for metabolic reprogramming, which in turn supports proliferation and survival of schwannomas. Driven by strong preliminary data we will elucidate the mechanism by which Tyr nitration regulates complex IV expression and activity (Aim 1); and determine the specific nitrated proteins and mechanisms that promote schwannoma metabolic reprogramming and growth (Aim 2). The proposed research is highly innovative, because it will identify concept-advancing and exceptional novel targets for drug development that are present in tumors but not in normal tissues. Furthermore, these findings are of high significance to human disease, since they may pave the way to completely new and efficacious treatment modalities, not only for NF2, but also for other solid tumors in the future.

项目摘要 神经纤维瘤病2型（NF2）是神经系统的令人衰弱的医学肿瘤障碍 由编码梅林肿瘤抑制剂的基因的突变灭活引起。 NF2患者发展 整个神经系统中没有药理治疗的多个schwannomas。 患者接受了令人衰弱的重复侵入性手术，以清除或延伸 神经，有可能永久性神经损伤。越来越多的证据表明通过活性氮氧化 物种是肿瘤生长的主要贡献者，但特定的氧化修饰和靶蛋白 介导的肿瘤活性尚不清楚。我们的目标是揭示调解的新型机制 NF2中细胞增殖的失调，并确定可能用作氧化修饰的蛋白 NF2和其他肿瘤的肿瘤定向的非侵入性治疗靶标。 我们令人兴奋的初步发现表明，一种这种氧化修饰，酪氨酸（Tyr）硝化， 有选择地支持Schwannoma细胞存活，并通过 降低氧化磷酸化复合物IV水平和活性，同时增加糖酵解和 谷氨酰胺溶解。此外，我们确定了31种schwannomas中的内源性硝化蛋白，包括Hsp90， 当硝化（转录因子GABP）硝化时，我们显示的线粒体呼吸降低了 负责调节复杂的IV表达和5种参与的肿瘤蛋白 在NF2中放松管制的信号通路。因此，我们将检验以下假设 NF2中的蛋白质失调可导致的线粒体呼吸和信号通路 代谢重编程，进而支持Schwannomas的增殖和存活。由 强大的初步数据我们将阐明Tyr Nitration调节复合物IV的机制 表达和活动（目标1）；并确定促进的特定硝化蛋白质和机制 Schwannoma代谢重编程和生长（AIM 2）。 拟议的研究具有很高的创新性，因为它将确定概念上的侵略和杰出的小说 肿瘤中存在的药物发育靶标，但不存在于正常组织中。此外，这些发现 对人类疾病具有很高的意义，因为它们可能为全新有效的道路铺平道路 治疗方式不仅针对NF2，而且对其他实体瘤的治疗方式。