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积木，并产生重要的 细胞信号分子，包括活性物质。当调控失调时，这些通路可能会导致 包括脑瘤在内的脑部病理。我们确定了一个涉及GTP的生物合成途径 作为限速步骤的环水解酶I(GCH1)有助于脑肿瘤的生长，并在 肿瘤干细胞亚群。在患者样本数据集中，GCH1水平的增加也与 结果很差。这些数据表明了理解生物和分子作用的重要性。 GCH1。因此，我们建议确定GCH1是否对调节体内活性物种平衡起关键作用 胶质瘤和维持肿瘤干细胞特性。GCH1潜在的新型下游介体 效果将得到验证。GCH1的药理和遗传抑制将决定GCH1的靶向是否 足以单独或与标准护理相结合来减少胶质瘤的生长。我们期待着这些研究 将决定是否应该进一步研究GCH1或同一生物合成途径中的另一种分子 作为疗效或治疗反应的生物标记物。我们希望我们的研究将为我们提供更大的 了解脑部疾病中代谢改变的机制，并为未来的研究提供新的信息 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.