Biological Effects and Mechanistic Actions of the Natural Disaccharide and Dietary Supplement, Trehalose.

天然二糖和膳食补充剂海藻糖的生物效应和机理作用。

• 批准号: 9809962
• 负责人: Brian Jesse DeBosch
• 金额: $ 23.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809962
• 关键词: Attenuated; Autophagocytosis; Biological; Biological Products; Caloric Restriction; Cardiovascular Diseases; Catabolism; Clinical; Complementary Health; Complementary therapies; Consumption; Data; Development; Diabetes Mellitus; Diet; Disaccharides; Engineering; Excipients; Exposure to; Extrahepatic; Fasting; Fatty Liver; Fatty acid glycerol esters; Genes; Genetic; Genetic Transcription; Glucose Transporter; Goals; Grant; Health; Health Promotion; Hepatic; Hepatocyte; In Vitro; Individual; Industrialization; Intermittent fasting; Laboratories; Literature; Liver; Longevity; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mus; Natural Products; Neurodegenerative Disorders; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phytochemical; Prevention; Preventive; Proteins; Reducing diet; Reporting; Research; Retinal Diseases; Rodent Model; Signal Pathway; Signal Transduction; Techniques; Testing; Therapeutic; Therapeutic Effect; Traction; Transcription Coactivator; Transplant-Related Disorder; Trehalase; Trehalose; Vascular Diseases; analog; dietary supplements; disorder prevention; fasting glucose; glucose transport; healthspan; human model; improved; in vivo; liver metabolism; liver transplantation; microbial; mimetics; mouse model; next generation; non-alcoholic fatty liver disease; novel; novel therapeutics; prevent; programs; response; therapeutic target; tool; transcription factor; transport inhibitor

Trehalose is a widely consumed, naturally-occurring biopharmaceutical and dietary supplement, which is widely purported to have health-promoting effects in retinal, neurodegenerative, vascular and metabolic disease. The mechanism of action of this promising phytochemical and disaccharide, however, remains incompletely understood. Understanding how trehalose exerts its therapeutic and preventive effects is important because it allows patients and clinicians to best predict the optimal contexts in which it should be deployed. Moreover, because we demonstrated that trehalose appears to act through broad, fasting-like, networked mechanisms to mitigate metabolic disease, dissecting fundamental actions of trehalose promises to inform next-generation compounds that leverage these same mechanisms, and to illuminate basic aspects underlying the therapeutic effects of adaptive fasting itself. Indeed the adaptive hepatic fasting response is gaining traction as a therapeutic target against non-alcoholic fatty liver disease (NAFLD), which afflicts approximately one billion individuals worldwide. Our long-term goal is to understand adaptive liver metabolism during fasting to produce new therapies against NAFLD. Our immediate research objective is to define the biological effects and mechanism of action of the natural compound and fasting mimetic, trehalose. Three key pieces of new data substantiate our approach: First, blocking hepatic glucose transport induces the hepatocyte glucose fasting response, and this is sufficient to convey the therapeutic effects of generalized fasting on NAFLD. Second, trehalose, is a hepatic glucose transport inhibitor that reduces diet-induced NAFLD in mice. Third, trehalose activates canonical fasting-like signaling pathways in association with its action to prevent and reverse diet-induced NAFLD. We will therefore directly test the central hypothesis that trehalose coordinately induces canonical fasting pathways to modulate hepatic metabolism. Our Specific Aims are to: 1) Define mechanistic contributions of hepatic fasting signaling and autophagy (both of which are central effector pathways of the fasting response) to the biological actions of trehalose, and 2) Delineate interactions between host and microbial trehalose catabolism, and the biological actions of trehalose. Completing these studies will: 1) illuminate basic principles of hepatic glucose fasting, 2) catalyze development of next-generation biopharmaceuticals which leverage these same fasting-like mechanisms, and 3) inform optimal contexts in which to deploy trehalose as a natural, health-promoting dietary supplement and preventative against metabolic disease.

海藻糖是一种广泛使用的天然生物制药和膳食补充剂，广泛声称对视网膜、神经退行性、血管和代谢疾病具有促进健康的作用。然而，这种有前途的植物化学物质和二糖的作用机制仍不完全清楚。了解海藻糖如何发挥其治疗和预防作用是非常重要的，因为它使患者和临床医生能够最好地预测其应用的最佳环境。此外，由于我们证明海藻糖似乎通过广泛的，类似禁食的网络机制来缓解代谢疾病，因此解剖海藻糖的基本作用有望为利用这些相同机制的下一代化合物提供信息，并阐明适应性禁食本身治疗效果的基本方面。事实上，适应性肝脏禁食反应作为非酒精性脂肪性肝病（NAFLD）的治疗靶点正在获得牵引力，NAFLD在全球范围内困扰着大约10亿人。我们的长期目标是了解禁食期间的适应性肝脏代谢，以产生针对NAFLD的新疗法。我们的近期研究目标是确定天然化合物和禁食模拟物海藻糖的生物学效应和作用机制。三个关键的新数据证实了我们的方法：首先，阻断肝葡萄糖转运诱导肝细胞葡萄糖禁食反应，这足以传达全面禁食对NAFLD的治疗作用。其次，海藻糖是一种肝葡萄糖转运抑制剂，可减少小鼠饮食诱导的NAFLD。第三，海藻糖激活与其预防和逆转饮食诱导的NAFLD的作用相关的典型禁食样信号通路。因此，我们将直接测试海藻糖协同诱导典型禁食途径以调节肝脏代谢的中心假设。我们的具体目标是：1）定义肝脏禁食信号传导和自噬（两者都是禁食反应的中心效应途径）对海藻糖生物学作用的机制贡献，2）描述宿主和微生物海藻糖催化剂之间的相互作用，以及海藻糖的生物学作用。完成这些研究将：1）阐明肝葡萄糖禁食的基本原理，2）促进利用这些相同的禁食机制的下一代生物药物的开发，3）告知将海藻糖作为天然，促进健康的膳食补充剂和预防代谢疾病的最佳环境。