Biosynthetic Metabolic Pathway Regulation of Glioma Growth

神经胶质瘤生长的生物合成代谢途径调节

基本信息

批准号：
10057274
负责人：
Anita Borton Hjelmeland
金额：
$ 37.93万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057274
关键词：
Adult Age Antioxidants Biological Biological Markers Brain Diseases Brain Neoplasms Brain Pathology CD44 gene Cancer Etiology Cell Maintenance Cells Characteristics Clinical Complementary DNA DNA Repair Data Data Set Enzymes Equilibrium Future GTP Cyclohydrolase I Genetic Genetic Transcription Glioblastoma Glioma Growth Guanosine Triphosphate In Vitro Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Mediator of activation protein Messenger RNA Metabolic Pathway Metabolism Modeling Molecular Mus Nitric Oxide Nitrogen Outcome Oxidative Stress Oxygen Pathway interactions Patient-Focused Outcomes Patients Pharmacology Phenotype Phosphorylation Prediction of Response to Therapy Primary Brain Neoplasms Prognosis Proteins Publications Radiation therapy Radio Recurrent tumor Regulation Role Sampling Serine Signal Transduction Signaling Molecule Specimen Superoxides Therapeutic Tissues Tumor Stem Cells Xenograft procedure cell growth chemotherapy childhood cancer mortality detector genetic signature improved in vivo inhibitor/antagonist irradiation member molecular subtypes novel novel strategies overexpression patient subsets preclinical trial prevent small hairpin RNA small molecule standard of care stem cell growth stem cells survival outcome temozolomide tetrahydrobiopterin therapy resistant treatment response treatment strategy tumor tumor growth tumor heterogeneity tumor metabolism tumorigenic

项目摘要

ABSTRACT Biosynthetic metabolic pathways provide the building blocks required for cell growth and generate important cell signaling molecules, including reactive species. When dysregulated, these pathways can contribute to brain pathologies including brain tumors. We determined that one biosynthetic pathway involving GTP cyclohydrolase I (GCH1) as the rate-limiting step contributes to the growth of brain tumors and is elevated in the neoplastic stem cell subpopulation. In patient sample datasets, increased levels of GCH1 also correlate with poor outcomes. These data suggest the importance of understanding the biological and molecular roles of GCH1. We have therefore proposed to determine if GCH1 is critical for regulating reactive species balance in glioma and maintaining neoplastic stem cell characteristics. Potential novel downstream mediators of GCH1 effects will be validated. Pharmacologic and genetic inhibition of GCH1 will determine if targeting of GCH1 is sufficient to decrease glioma growth alone or in combination with standard of care. We anticipate these studies will determine if GCH1 or another molecule in the same biosynthetic pathway should be a further investigated as a biomarker for either outcome or therapeutic response. We hope that our studies will provide a greater understanding of the mechanisms through which metabolism is altered in brain disease and inform future novel treatment strategies.

抽象的生物合成代谢途径提供细胞生长所需的构建模块并产生重要的细胞信号分子，包括活性物质。当失调时，这些途径可能会导致脑部病变，包括脑肿瘤。我们确定了一种涉及 GTP 的生物合成途径环水解酶 I (GCH1) 作为限速步骤，有助于脑肿瘤的生长，并且在肿瘤干细胞亚群。在患者样本数据集中，GCH1 水平的增加也与结果不佳。这些数据表明了解其生物学和分子作用的重要性 GCH1。因此，我们建议确定 GCH1 对于调节反应性物种平衡是否至关重要神经胶质瘤和维持肿瘤干细胞特征。 GCH1 潜在的新型下游介质效果将得到验证。 GCH1 的药理学和遗传抑制将决定 GCH1 的靶向是否有效单独或与标准护理相结合足以减少神经胶质瘤的生长。我们预计这些研究将确定是否应进一步研究 GCH1 或同一生物合成途径中的另一个分子作为结果或治疗反应的生物标志物。希望我们的研究能为大家提供更多帮助了解脑部疾病中新陈代谢改变的机制，并为未来的小说提供信息治疗策略。