Hepatic kisspeptin receptor signaling in nonalcoholic fatty liver

非酒精性脂肪肝中的肝脏 Kisspeptin 受体信号传导

基本信息

批准号：
10389827
负责人：
Stephania Guzman
金额：
$ 3.6万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2022-10-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389827
关键词：
Affect Agonist Alcohols Binding Biochemical Bioinformatics Biology Blood Cicatrix Cirrhosis Clinical Clinical Data Coupled Data Deuterium Development Diet Disease Exhibits Fatty Liver Fatty acid glycerol esters Fibrosis GDF15 gene GTP-Binding Proteins Goals Hepatic Hepatocyte High Fat Diet Homeostasis Inflammation Inflammatory Insulin Resistance KISS1 gene KISS1R gene Knockout Mice Lead Ligands Lipids Liver Liver Fibrosis Mass Spectrum Analysis Mediator of activation protein Messenger RNA Metabolic Metabolic Diseases Metabolic syndrome Molecular Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Pathogenesis Pathway interactions Patients Peptides Persons Pharmaceutical Preparations Pharmacology Pharmacotherapy Plasma Prevalence Preventive treatment Primary carcinoma of the liver cells Proteins Receptor Activation Receptor Signaling Research Personnel Role Signal Transduction Source Steatohepatitis Testing Tissues Triglycerides Water Work chronic liver disease comorbidity fibroblast growth factor 21 gain of function improved in vivo inflammatory marker lipid biosynthesis lipid metabolism liver development liver transplantation metabolomics mortality mouse model non-alcoholic fatty liver non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel prevent receptor sensor therapeutic development therapeutic target

项目摘要

PROJECT SUMMARY The increasing prevalence of obesity in the U.S.A. is associated with metabolic comorbidities such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), a disease characterized by excess liver fat accumulation in people who drink little to no alcohol. Although there are many medications approved for T2D, no medications are approved for NAFLD, which is now the leading cause of chronic liver disease and fastest-growing reason for liver transplantation. The first stage of NAFLD is steatosis (fatty liver), that can progress to non- alcoholic steatohepatitis (NASH) where fat accumulation in the liver is associated with inflammation and scarring. As the liver cells are gradually replaced by scar tissue, the liver stops functioning properly. The liver produces a peptide known as kisspeptin (KP) that circulates in the blood. KP binds a protein known as the kisspeptin 1 receptor (KISS1R). Although KISS1R is expressed in the liver, its function is unknown. Our new pilot data has revealed that KP/KISS1R signaling can inhibit fat accumulation in the liver. Using genetically modified mouse models and plasma derived from NAFLD patients, the proposed work will determine whether KISS1R signaling prevents the development of NAFLD and the underlying mechanisms. In Aim 1, we will investigate the mechanisms by which hepatic KISS1R signaling inhibits lipogenesis. In Aim 2, we will determine the effect of increasing KISS1R signaling on the development of NASH and fibrosis. Collectively, these clinically translational findings may identify KISS1R as a novel target for the preventive treatment against the development of NAFLD.

项目概要美国肥胖症患病率的增加与代谢合并症有关例如 2 型糖尿病 (T2D) 和非酒精性脂肪肝 (NAFLD) 其特点是饮酒很少或不饮酒的人肝脏脂肪堆积过多。虽然有许多药物被批准用于治疗 T2D，但没有药物被批准用于治疗 NAFLD，这现在是慢性肝病的主要原因，也是肝病增长最快的原因移植。 NAFLD 的第一阶段是脂肪变性（脂肪肝），可进展为非脂肪肝酒精性脂肪性肝炎（NASH），肝脏中的脂肪堆积与炎症和疤痕。随着肝细胞逐渐被疤痕组织取代，肝脏停止运转正常运作。肝脏产生一种称为 Kisspeptin (KP) 的肽，在肝脏中循环血。 KP 结合一种称为 Kisspeptin 1 受体 (KISS1R) 的蛋白质。虽然KISS1R是在肝脏中表达，其功能未知。我们的新试点数据显示 KP/KISS1R 信号传导可以抑制肝脏中的脂肪积累。使用转基因小鼠模型和来自 NAFLD 患者的血浆，拟议的工作将确定 KISS1R 是否信号传导可防止 NAFLD 的发展及其潜在机制。在目标 1 中，我们将研究肝脏 KISS1R 信号传导抑制脂肪生成的机制。在目标 2 中，我们将确定增加 KISS1R 信号传导对 NASH 和纤维化发展的影响。总的来说，这些临床转化研究结果可能会将 KISS1R 确定为新的靶点针对 NAFLD 发展的预防性治疗。