mTORC1 signaling in aging and metabolism

衰老和代谢中的 mTORC1 信号传导

• 批准号: 9357510
• 负责人: BRIAN K KENNEDY
• 金额: $ 51.21万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357510
• 关键词: Adipose tissue; Age; Aging; Amino Acids; Anti-Inflammatory Agents; Atrophic; Autophagocytosis; Brain; Brown Fat; Carbohydrates; Cell Culture Techniques; Cellular Metabolic Process; Clinical; Complex; Data; Diabetes Mellitus; Diet; Disease; Dose; Drug Targeting; EIF4EBP1 gene; Eukaryotic Cell; Exhibits; FGF21 gene; FRAP1 gene; Fatty acid glycerol esters; Female; Functional disorder; Gender; Genetic; Glucose; Glucose Intolerance; Growth; High Fat Diet; Human; Hypoxia; Inflammation; Insulin; Insulin Resistance; Intervention; Life; Link; Longevity; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mouse Strains; Mus; Muscle; Muscle function; Nutrient; Obesity; Organism; Overnutrition; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Process; Production; Protein Kinase; Regulation; Resistance; Respiration; Ribosomal Protein S6 Kinase; Role; Signal Pathway; Signal Transduction; Sirolimus; Skeletal Muscle; Specificity; Stress; Testing; Tissues; Transgenic Mice; Transgenic Model; Transgenic Organisms; Yeasts; adenylate kinase; age related; biological adaptation to stress; detection of nutrient; dimorphism; fly; gene therapy; improved; insight; male; mouse model; multicatalytic endopeptidase complex; normal aging; novel; overexpression; protective effect; respiratory; response; restoration

Project Summary/Abstract Many signaling pathways linked to aging are linked to the regulation of metabolic signaling and stress response pathways. For instance, the target of rapamycin (TOR) pathway is an evolutionarily-conserved nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Two complexes, mTORC1 and 2, have overlapping upstream regulators and downstream effectors. Reduced mTOR signaling, either by genetic intervention or with the clinically approved drug rapamycin, extends longevity in mice (as well as yeast, worms and flies) and delays many pathologies of aging. Given its central role in aging and metabolism, it is critical to understand how different perturbations of the mTOR pathway impact aging and metabolism. Here, we use mouse models and cell culture studies to test one of the major downstream targets of mTORC1, 4E-BP1. Justifying the emphasis on 4E-BP1, enhanced 4E-BP activity is associated with lifespan extension in worms and flies, and we find that transgenic mice overexpressing 4E-BP1 are resistant to high fat diet-induced metabolic dysfunction. We will employ multiple mouse models of 4E-BP1 overexpression in both overnutrition and aging studies. Preliminary data indicates that an inflammation-induced loss of 4E-BP1 expression in the context of a high fat diet underlies the specific propensity of males to become glucose intolerant and insulin resistant. We will determine the mechanisms underlying this gender dimorphism and its impact on the mTOR pathway. Gender-specific responses to diet and aging are rampant in mouse models and in humans, but the underlying causes of gender-specificity is largely unknown. In addition, we will determine why muscle specific activation of 4E-BP1 preserves both skeletal muscle function and brown fat content during overnutrition and aging, focusing on recent findings linking the benefits to skeletal muscle production and secretion of the myokine, FGF21. Together, these studies will yield several new insights regarding the specifics of mTOR signaling in the context of aging and metabolism, providing a better understanding about how this pathway modulates aging and linking modulation of the mTOR pathway to other pharmacologic interventions in aging.

项目摘要/摘要 与老化有关的许多信号通路与代谢信号和应力的调节有关 响应途径。例如，雷帕霉素（TOR）途径的靶标是一种进化保存的 营养感应蛋白激酶，可调节所有真核细胞的生长和代谢。两个复合物， MTORC1和2具有重叠的上游调节器和下游效应子。 MTOR信号降低， 通过遗传干预或使用临床认可的药物雷帕霉素，可以延长小鼠的寿命（也 作为酵母，蠕虫和苍蝇），并延迟了许多衰老的病理。鉴于其在衰老中的核心作用 代谢，了解MTOR途径的不同扰动如何影响衰老和 代谢。在这里，我们使用小鼠模型和细胞培养研究来测试主要下游目标之一 MTORC1，4E-BP1。证明对4e-bp1的重点是合理的，增强的4e-bp活动与寿命有关 蠕虫和苍蝇的延伸，我们发现过表达4e-bp1的转基因小鼠对高脂肪具有抗性 饮食引起的代谢功能障碍。我们将在两者中采用多种4e-bp1过表达的鼠标 营养和衰老研究。初步数据表明炎症引起的4E-BP1损失 在高脂肪饮食的背景下，表达雄性的特定倾向是​​葡萄糖的特定倾向 不耐受和胰岛素耐药。我们将确定这种性别二态性及其的机制 对MTOR途径的影响。在小鼠模型中，对饮食和衰老的性别特异性反应猖ramp 在人类中，但是性别特异性的根本原因在很大程度上是未知的。此外，我们将确定 为什么4E-BP1的肌肉特异性激活在 营养和衰老，重点是将益处与骨骼肌肉产生联系起来的最新发现和 肌动物的分泌，FGF21。这些研究将共同​​产生一些有关 MTOR信号的细节在衰老和代谢的背景下，提供了更好的了解 该途径如何调节MTOR途径的衰老和连接到其他药物的调制 衰老的干预措施。