肥胖是威胁人类健康的全球问题，引起肥胖的分子机理不清楚。本团队研究发现，Obg家族和YchF亚家族P环GTP酶（OLA1）是一种tRNA结合蛋白，其GTPase活性能够被空载的tRNA所激活，此种tRNA是氨基酸缺乏时替代分子。我们发现敲除或敲低OLA1的细胞AA饥饿应答减弱。而且发现OLA1 KO小鼠体型小且瘦； OLA1可能是GSK3β的一种新的抑制物。因此，我们提出科学假说，OLA1可能是第三代饥饿时细胞对氨基酸需求的传感器，并且可能是抗肥胖药物新的靶位点。为此提出以下三个目标：（1）通过体外细胞实验和体内OLA1 KO小鼠实验确定OLA1是氨基酸的饥饿传感器；（2）通过稳定性敲除OLA1产生的瘦型小鼠研究OLA1是不是全身能量代谢的关键调节因素；（3）通过建立可诱导的OLA1敲除小鼠来研究OLA1是否可以作为抗肥胖新的靶位点。此研究将为开发以OLA1为靶点的抗肥胖新药奠定科学基础。

Obesity is a life-threaten disease, which has been a serious human health concern world-wide, and the exact molecular mechanism that causes obesity is unclear. A recent study from our group found that the P-loop GTPase (OLA1) of the Obg family and the YchF subfamily is a tRNA-binding protein whose GTPase activity can be activated by the unloaded tRNA, which is an alternative molecule when the amino acid is deficient. We found that knockout or knockdown of OLA1 cells decreased the AA starvation response At the cellular level, and found that OLA1 KO mice were small in size and lean, and OLA1 may be also found a novel inhibitor of GSK3β. We thus hypothesized that OLA1 may be the third generation of nutrient sensor as cells respond to amino acid deficient, and may be a new target for anti-obesity drugs. We then propose three specific aims in order to test our hypothesis: 1) to identify that the OLA1 is a starvation sensor for deficiency in amino acids by in vitro cell experiments and in vivo OLA1 KO mice; 2) to determine whether OLA1 is a key metabolic regulator governing whole-body energy metabolism in the lepthenotype mice produced by stably knocked-out OLA1; and 3) to investigate whether OLA1 can be developed as a new target of anti-obesity drugs by establishment of an inducible OLA1 knockout mouse. Completion of this project will lay the scientific foundation for development of anti-obesity new drugs targeting OLA1 in future.