R-spondin1-LGR4 Signaling and Ischemia/Reperfusion Injury in Steatotic Liver

脂肪肝中的 R-spondin1-LGR4 信号转导和缺血/再灌注损伤

• 批准号: 9896813
• 负责人: MICHAEL W. MULHOLLAND
• 金额: $ 41.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896813
• 关键词: Adult; Affect; American; Area; Biological; Cells; Complex; Couples; Data; Development; Discipline; Energy Supply; FRAP1 gene; Fatty Liver; G-Protein-Coupled Receptors; GTP-Binding Proteins; Health; Hepatic; Hepatic Tissue; Hepatocyte; Injury; Leucine-Rich Repeat; Ligands; Lipids; Liver; Medical; Molecular; Morbidity - disease rate; Names; Nutrient; Pathway interactions; Patients; Physiological; Physiology; Predisposition; Prevention; Prevention strategy; Protein Family; Reperfusion Injury; Signal Pathway; Signal Transduction; Societies; Stress; System; Techniques; Time; Transgenic Organisms; beta catenin; hypoxia inducible factor 1; insight; liver injury; member; mortality; non-alcoholic fatty liver disease; novel; receptor; sensor; treatment strategy

Project Summary Non-alcoholic fatty liver disease represents a group of conditions associated with excessive lipid accumulation in hepatocytes. Hepatic steatosis affects almost 30% of adults and imposes a major health burden on American society. Non-alcoholic fatty liver disease increases morbidity and mortality associated with injury or physiological stress, and thus is a concern for all medical disciplines. Our preliminary studies have identified a novel molecular pathway and novel cellular mechanisms that couple long-term energy supply to steatosis and injury. Our studies demonstrate for the first time that a member of the leucine-rich repeat-containing G protein- coupled receptors, LGR4, is expressed in hepatocytes. R-spondin family proteins were recently identified as ligands for LGR4. Our preliminary data also indicate that R-spondin1 is produced by hepatocytes and that R- spondin1-LGR4 signaling is present in the liver. Distinct from classical G protein-coupled receptors which act via G proteins, hepatic LGR4 functions mainly through Wnt/β-catenin signaling. Further, preliminary studies indicate that the mechanistic target of rapamycin complex 1 (mTORC1) in liver couples long-term nutrient status to R-spondin1-LGR4 expression. Steatosis down regulates hepatic R- spondin1/LGR4 and renders hepatic tissue more vulnerable to injury. We propose to investigate the function of the hepatic R-spondin1-LGR4 system using cell biological and transgenic techniques. Completion of this proposal will advance a completely new area of hepatic physiology and will provide novel insights into to liver injury.

项目摘要 非酒精性脂肪性肝病代表了一组与脂质过度积聚相关的疾病 在肝细胞中。肝脏脂肪变性影响近30%的成年人，并对他们造成重大的健康负担。 美国社会非酒精性脂肪肝增加了与损伤或 生理压力，因此是所有医学学科关注的问题。我们的初步研究发现 新的分子途径和新的细胞机制，将长期能量供应与脂肪变性相结合， 损伤 我们的研究首次证明了富含亮氨酸重复序列的G蛋白的一个成员- 偶联受体LGR 4在肝细胞中表达。R-spondin家族蛋白最近被鉴定为 LGR 4的配体。我们的初步数据还表明，R-spondin 1是由肝细胞产生的，而R-spondin 1是由肝细胞产生的。 Spondin 1-LGR 4信号传导存在于肝脏中。与经典的G蛋白偶联受体不同， 肝脏LGR 4主要通过Wnt/β-catenin信号通路发挥作用。 此外，初步研究表明，雷帕霉素复合物1（mTORC 1）在肝脏中的机制靶点 将长期营养状态与R-spondin 1-LGR 4表达相结合。脂肪变性下调肝脏R- spondin 1/LGR 4并使肝组织更容易受到损伤。我们建议研究函数 的肝R-spondin 1-LGR 4系统使用细胞生物学和转基因技术。完成本 该提案将推进肝脏生理学的一个全新领域，并将为肝脏提供新的见解 损伤