Biosynthetic Metabolic Pathway Regulation of Glioma Growth

摘要 生物合成代谢途径提供细胞生长所需的构件，并产生重要的 细胞信号分子，包括活性物质。当失调时，这些途径可以有助于 包括脑肿瘤在内的脑病理学。我们确定一个涉及GTP的生物合成途径 环水解酶I（GCH 1）作为限速步骤有助于脑肿瘤的生长，并且在脑肿瘤中升高。 肿瘤干细胞亚群。在患者样本数据集中，GCH 1水平的增加也与 结果很差。这些数据表明，了解生物学和分子作用的重要性， GCH 1.因此，我们建议确定GCH 1是否对调节反应性物种平衡至关重要， 胶质瘤和维持肿瘤干细胞特性。潜在的新型GCH 1下游介质 效果将得到验证。GCH 1的药理学和遗传学抑制将决定GCH 1的靶向作用是否是有效的。 足以单独或与标准护理组合降低胶质瘤生长。我们预计这些研究 将确定是否应该进一步研究GCH 1或相同生物合成途径中的另一种分子 作为结果或治疗反应的生物标志物。我们希望，我们的研究将提供一个更大的 了解代谢在脑部疾病中改变的机制，并为未来的小说提供信息。 治疗策略。

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.