权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel Components of the mTORC1 and mTORC2 Pathways

mTORC1 和 mTORC2 通路的新成分

基本信息

批准号：
10114955
负责人：
JONATHAN S. WEISSMAN
金额：
$ 48.75万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10114955
关键词：
Adipose tissue Aging Amino Acids Animals Autophagocytosis Biochemistry Biological Models Biological Process Biomass Branched-Chain Amino Acids CRISPR screen Catabolic Process Catalytic Domain Cells Central Vein Complex Cultured Cells Cytosol Data Diabetes Mellitus Diet Disease Drug Targeting Engineering Epilepsy Epitopes Equilibrium Essential Amino Acids FRAP1 gene Fasting Genetic Genetic Screening Genetic Suppression Genetically Engineered Mouse Gluconeogenesis Goals Grant Growth Growth Factor Guanosine Triphosphate Phosphohydrolases Hepatic lobule Hepatocyte In Vitro Individual Lead Leucine Lipids Liver Lobule Logic Longevity Lysosomes Malignant Neoplasms Mammals Metabolism Methodology Molecular Biology Multiprotein Complexes Mus Nucleotides Nutrient Nutritional Organism Pathway interactions Perfusion Pharmacology Phosphotransferases Physiological Physiology Play Portal triad Portal vein structure Process Protein Kinase Proteins Proteomics Regulation Role Signal Pathway Signal Transduction Signaling Protein Sirolimus Skeletal Muscle Starvation Stimulus Stress Surface System Testing Tissues Unhealthy Diet Valine Weight Work cell growth deprivation detection of nutrient feeding follow-up human disease in vivo interdisciplinary approach liver metabolism mTOR protein metabolomics novel prevent protein complex response sensor therapeutic target

项目摘要

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.

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（mTORC1）和2（mTORC2），它们控制通路的不同分支并优先响应不同的刺激。mTORC1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mTORC1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mTORC1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。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase.

DOI：
10.1016/j.immuni.2017.06.005
发表时间：
2017-06-20
期刊：
Immunity
影响因子：
32.4
作者：
Ersching J;Efeyan A;Mesin L;Jacobsen JT;Pasqual G;Grabiner BC;Dominguez-Sola D;Sabatini DM;Victora GD
通讯作者：
Victora GD

mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.

MTORC1通过需要液泡H（+）ATPase的内而外机制感测。

DOI：
10.1126/science.1207056
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Zoncu R;Bar-Peled L;Efeyan A;Wang S;Sancak Y;Sabatini DM
通讯作者：
Sabatini DM

The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway.

DOI：
10.1016/j.cmet.2017.07.001
发表时间：
2017-08-01
期刊：
Cell metabolism
影响因子：
29
作者：
Wolfson RL;Sabatini DM
通讯作者：
Sabatini DM

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP.

DOI：
10.1158/0008-5472.can-16-0155
发表时间：
2016-12-15
期刊：
Cancer research
影响因子：
11.2
作者：
Muranen T;Selfors LM;Hwang J;Gallegos LL;Coloff JL;Thoreen CC;Kang SA;Sabatini DM;Mills GB;Brugge JS
通讯作者：
Brugge JS

Loss of hepatic DEPTOR alters the metabolic transition to fasting.

DOI：
10.1016/j.molmet.2017.02.005
发表时间：
2017-05
期刊：
Molecular metabolism
影响因子：
8.1
作者：
Caron A;Mouchiroud M;Gautier N;Labbé SM;Villot R;Turcotte L;Secco B;Lamoureux G;Shum M;Gélinas Y;Marette A;Richard D;Sabatini DM;Laplante M
通讯作者：
Laplante M