Novel Components of the mTORC1 and mTORC2 Pathways

MTOR激酶是控制物质积累的信号通路的中心组成部分 和新陈代谢，以响应有机体的营养状态。在许多情况下，该途径被解除了管制 常见的人类疾病，包括癌症、癫痫和糖尿病，也被公认为 调节衰老过程。对mTOR的药理或遗传抑制是最好的- 经过验证的延长各种生物寿命的方法。MTOR蛋白激酶是 药物雷帕霉素和两个大型蛋白质复合体的催化亚单位mTOR复合体1的靶点 (MTORC1)和2(MTORC2)，它们控制通路的单独分支并优先反应 对不同的刺激。MTORC1对多种信号做出反应，包括多种类型的生长因子， 营养，强调和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、脂类合成和自噬。最近，我们 发现了mTORC1感知营养的许多成分，我们才刚刚开始 了解营养感应通路在体内的作用。我们的初步数据显示 营养素对mTORC1的适当调节对小鼠适应低必需饮食至关重要 氨基酸亮氨酸。此外，我们有证据表明，mTORC1在意想不到的空间上受到控制 体内组织中的方式和体内新的调节机制仍有待发现。 我们提议的工作的目标是理解为什么mTORC1感知亮氨酸的能力 剥夺对小鼠适应无亮氨酸饮食很重要(目标1)，而 在组织生理学和新陈代谢控制中区分营养传感(目标2)。在……里面 此外，我们将利用体内蛋白质组学和遗传学来确定肝脏中新的mTORC1调节因子 (目标3)。我们将通过利用生物化学的多学科方法来实现我们的目标， 代谢组学、蛋白质组学、分子生物学和小鼠工程。我们的结果应该会增加我们的 了解体内的中央生长调节因子，并揭示可能 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.