氨调控mTORC信号通路的分子机制研究

氨是生物体中普遍存在的代谢物，主要由氨基酸以及含氮化合物代谢生成。肿瘤细胞如何应对其快速代谢过程中产生的大量的氨，以及氨的累积有何生物学功能，目前研究尚不清楚。mTOR是一个保守的Ser/Thr激酶，它的活性受到营养胁迫、能量应激和生长因子的调控，是肿瘤细胞增殖、存活的重要调控因子。我们的初步研究数据表明，氨的累积可以显著降低mTOR信号通路的活性并且抑制肿瘤细胞的增殖。为进一步确定氨对于肿瘤细胞的生理功能，本项目拟以多种肿瘤细胞为模型，利用细胞、分子和生化等方法，进行深入研究，主要包括以下两个方面：1）氨调控肿瘤细胞mTOR信号通路活性的分子机制；2）mTOR信号通路活性高低对氨所调控的肿瘤细胞命运的影响。期望通过以上两个方面的研究，阐明氨调控mTOR信号通路的机制和功能，为深入理解氨在肿瘤发生发展中的生物学功能提供实验依据，为肿瘤的临床治疗提供新的理论依据或靶点。

Ammonia is frequently generated in a body during nitrogen metabolism. Tumor cells usually have increased nutrient uptake and metabolic activity, and during which ammonia is concomitantly produced. However，it still remains unclear what outcomes might be caused by ammonia accumulation. The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that controls tumor cell proliferation and metabolism in response to nutrients, growth factors, and various metabolic stresses. Our recently studies reveal that ammonia may have a role in repressing the activity of mTOR signaling pathway. Therefore, we plan to investigate：1) the molecular mechanism(s) by which ammonia regulates mTOR signaling pathway in tumor cells, and (2) the role of mTOR signaling in ammonia-mediated tumor cell proliferation. By studying these, we hope to identify a pathologic function of ammonia, and potentially provide a theoretical basis for clinical treatment of tumor.