mTORC1 Regulation by Upstream Stimuli

摘要 哺乳动物雷帕霉素靶蛋白（mTOR）是一种进化上保守的丝氨酸/苏氨酸激酶，可检测多个 上游刺激来调节细胞生长、代谢和自噬。mTOR是一种 多蛋白复合物称为mTOR复合物1（mTORC 1）。mTORC 1激活升高在多个 人类疾病，包括癌症、2型糖尿病、代谢紊乱和神经变性。小分子 像雷帕霉素一样，靶向和抑制mTORC 1的药物在临床上的应用效果有限。因此， 调节mTORC 1的分子机制对于治疗mTORC 1介导的疾病至关重要。的 这项提议的总体目标是破译mTORC 1受以下因素调节的分子机制： 上游刺激。具体而言，该提案集中于通过氨基酸和G蛋白调节mTORC 1 偶联受体（GPCR）。我们预计，这项提案中的研究将对mTORC 1产生新的见解 通过上游刺激调节，并将发现新的治疗靶点，以扰乱mTORC 1介导的疾病。

ABSTRACT The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase that senses multiple upstream stimuli to regulate cell growth, metabolism, and autophagy. mTOR is the catalytic component of a multi-protein complex called mTOR complex 1 (mTORC1). Elevated mTORC1 activation is common in multiple human disease including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Small molecules like rapamycin that target and inhibit mTORC1 are used in the clinic with limited success. Thus, deciphering the molecular mechanisms by which mTORC1 is regulated is crucial to treat mTORC1-mediated disease. The overall objective of this proposal is to decipher the molecular mechanisms by which mTORC1 is regulated by upstream stimuli. Specifically, this proposal is focused on mTORC1 regulation by amino acids and G-protein coupled receptors (GPCRs). We anticipate that the studies in this proposal will yield new insights into mTORC1 regulation by upstream stimuli and will uncover novel therapeutic targets to perturb mTORC1-mediated disease.