Novel Components of the mTORC1 and mTORC2 Pathways

mTOR激酶是控制质量积累的信号通路的中心组分 和新陈代谢对有机体营养状态的反应。在许多情况下， 常见的人类疾病，包括癌症，癫痫和糖尿病，也是公认的， 调节衰老过程mTOR的药理学或遗传抑制是最好的- 增加各种生物寿命的有效方法。mTOR蛋白激酶是 药物雷帕霉素的靶点和两个大蛋白复合物mTOR复合物1的催化亚基 （mTORC 1）和2（mTORC 2），它们控制通路的不同分支并优先响应 不同的刺激。mTORC 1对不同的信号有反应，包括许多类型的生长因子， 营养素和压力，并调节主要合成代谢和分解代谢过程之间的平衡， 分别包括蛋白质、核苷酸和脂质合成以及自噬。最近我们 发现了mTORC 1感知营养的许多成分，我们才刚刚开始 了解体内营养感应途径的作用。初步数据显示， 通过营养物适当调节mTORC 1对于小鼠适应必需营养素含量低的饮食是必不可少的。 氨基酸亮氨酸此外，我们有证据表明，mTORC 1在空间上受到意外的控制， 在体内组织中的方式和新的体内调节机制仍有待发现。 我们提出的工作的目标是了解为什么mTORC 1的能力，以感亮氨酸 剥夺对于小鼠适应无亮氨酸饮食（Aim 1）是重要的， 组织生理学和代谢控制中的分区营养感测（目标2）。在 此外，我们将利用体内蛋白质组学和遗传学来鉴定肝脏中新的mTORC 1调节剂 (Aim 3）。我们将利用生物化学， 代谢组学、蛋白质组学、分子生物学和小鼠工程。我们的成果应该会增加我们的 了解体内的中枢生长调节因子，并揭示新的调节机制， 具有作为治疗靶点的价值。

The mTOR kinase is the central component of a signaling pathway that controls mass accumulation and metabolism in response to the nutritional state of organisms. The pathway is deregulated in many common human diseases, including cancer, epilepsy, and diabetes, and is also well established to modulate the aging process. Pharmacological or genetic suppression of mTOR is amongst the best- validated approaches for increasing the lifespan of diverse organisms. The mTOR protein kinase is the target of the drug rapamycin and the catalytic subunit of two large protein complexes, mTOR Complex 1 (mTORC1) and 2 (mTORC2), that control separate branches of the pathway and preferentially respond to different stimuli. mTORC1 responds to diverse signals, including many types of growth factors, nutrients, and stresses, and regulates the balance between major anabolic and catabolic processes, including protein, nucleotide, and lipid synthesis as well as autophagy, respectively. Recently, we discovered many of the components through which mTORC1 senses nutrients and we are just starting to understand the role of the nutrient-sensing pathway in vivo. Our preliminary data show that the appropriate regulation of mTORC1 by nutrients is essential for mice to adapt to diets low in the essential amino acid leucine. Moreover, we have evidence that mTORC1 is spatially controlled in unexpected ways in tissues in vivo and that novel in vivo regulatory mechanisms remain to be discovered. The goals of our proposed work are to understand why the capacity of mTORC1 to sense leucine deprivation is important for mice to adapt to a leucine-free diet (Aim 1) and the role of compartmentalized nutrient sensing in the control of tissue physiology and metabolism (Aim 2). In addition, we will exploit in vivo proteomics and genetics to identify novel mTORC1 regulators in the liver (Aim 3). We will accomplish our goals with a multi-disciplinary approach that exploits biochemistry, metabolomics, proteomics, molecular biology, and mouse engineering. Our results should increase our understanding of a central growth regulator in vivo and reveal novel regulatory mechanisms that may have value as therapeutic targets.