Glutamine Sensing by mTORC1

mTORC1 谷氨酰胺传感

基本信息

批准号：
9918924
负责人：
Jenna L Jewell
金额：
$ 32.09万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918924
关键词：
ADP-Ribosylation Factor 1 Amino Acid Transporter Amino Acids Arginine Autophagocytosis Biochemical Biological Biological Process Biology CCI-779 Cancer Cell Growth Catabolic Process Cell Proliferation Cell physiology Cells Clinic Colon Carcinoma Complex Couples Cyclic AMP-Dependent Protein Kinases Data Disease Equilibrium FRAP1 gene GTPase-Activating Proteins Glutamine Goals Guanine Nucleotide Exchange Factors Guanine Nucleotides Guanosine Triphosphate Phosphohydrolases Homeostasis Knock-out Leucine Lysosomes Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Membrane Metabolic Control Metabolic Diseases Metabolism Molecular Monomeric GTP-Binding Proteins Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Nutrient Organism Pathway interactions Phosphotransferases Physiological Process Protein Biosynthesis Protein Complex Subunit Proteins Regulation Reporting Role Signal Pathway Signal Transduction Starvation Stimulus Translations Treatment Efficacy base cancer cell cancer type cell growth combat detection of nutrient experimental study extracellular human disease insight interest new therapeutic target novel protein complex response sensor small molecule solute success therapeutic target trafficking

项目摘要

! Abstract Extracellular and intracellular nutrient availability is sensed by organisms in order to control metabolic processes and maintain proper cell growth. Disruption in nutrient sensing can be disastrous, often leading to human disease. Perhaps the most notable player in this process is the mammalian target of rapamycin (mTOR) protein kinase, a key component in the multi-subunit protein complex called mTOR complex 1 (mTORC1). Increased mTORC1 activation is common in many human diseases including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Small molecules such as rapamycin and rapamycin analogs (rapalogs) that inhibit mTORC1, are currently used in the clinic to treat disease with limited success. Therefore, elucidating the molecular mechanisms of mTORC1 regulation is of great interest in order to treat mTORC1 driven disease. Amino acids are the most powerful activator of mTORC1 and for several years were thought to activate mTORC1 exclusively through the Rag GTPases. We recently discovered a novel signaling pathway whereby glutamine signals to mTORC1 independent of the Rag GTPases, and requires another small GTPase, ADP ribosylation factor-1 (Arf1). Arf1 guanine nucleotide cycling is required for glutamine to promote mTORC1 lysosomal localization and activation. The potential significance of this discovery is underscored by the fact that cancer cells are often “addicted” to glutamine, in part through mTORC1, to fuel cell growth and proliferation. We have identified two new components involved in this pathway, a known Arf1 GAP (Specific Aim 1) and a poorly characterized solute carrier (SLC) glutamine transporter (Specific Aim 2). We propose to investigate the role of these two new components in glutamine-induced mTORC1 activation. Furthermore, we will determine the significance of these components in mTORC1-mediated biology and disease (Specific Aim 3). Thus, the overall objective of this proposal is to decipher the molecular mechanisms by which glutamine signals to mTORC1. We anticipate that the proposed studies will yield new insights into mTORC1 regulation by glutamine and will uncover therapeutic targets to perturb mTORC1-mediated disease. !

！抽象的生物体感知细胞外和细胞内营养的可用性，以控制代谢营养感应的破坏可能是灾难性的，通常会导致也许这一过程中最引人注目的参与者是雷帕霉素的哺乳动物靶标。 (mTOR) 蛋白激酶，是称为 mTOR 复合物 1 的多亚基蛋白复合物的关键成分 (mTORC1) 增加的 mTORC1 激活在许多人类疾病中很常见，包括 2 型癌症。糖尿病、代谢紊乱和神经退行性疾病，如雷帕霉素和雷帕霉素。抑制 mTORC1 的类似物（rapalogs）目前在临床上用于治疗疾病，但成效有限。因此，阐明 mTORC1 调节的分子机制对于治疗 mTORC1 驱动的疾病是 mTORC1 最强大的激活剂，多年来一直被认为是 mTORC1 驱动的疾病。被认为仅通过 Rag GTPases 激活 mTORC1 我们最近发现了一种新的信号传导。谷氨酰胺向 mTORC1 发出信号的途径独立于 Rag GTPases，并且需要另一个小 GTPase、ADP 核糖基化因子 1 (Arf1) Arf1 鸟嘌呤核苷酸循环是谷氨酰胺促进的必要条件。 mTORC1 溶酶体定位和激活强调了这一发现的潜在意义。事实上，癌细胞常常对谷氨酰胺“上瘾”，部分是通过 mTORC1 来促进细胞生长和我们已经确定了参与该途径的两个新成分，即已知的 Arf1 GAP（特异性）。目标 1) 和充分表征的溶质载体 (SLC) 谷氨酰胺转运蛋白（具体目标 2）。研究这两种新成分在谷氨酰胺诱导的 mTORC1 激活中的作用。将确定这些成分在 mTORC1 介导的生物学和疾病中的重要性（具体目标 3).因此，该提案的总体目标是破译其分子机制我们预计所提出的研究将对 mTORC1 产生新的见解。谷氨酰胺的调节，并将发现干扰 mTORC1 介导的疾病的治疗靶点。！