Understanding fatty liver disease using the zebrafish mutant, foie gras

使用斑马鱼突变体鹅肝了解脂肪肝

• 批准号: 7730540
• 负责人: Kirsten C Sadler Edepli
• 金额: $ 42.15万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730540
• 关键词: Acute; Alcohol abuse; Alcoholism; Alcohols; Alleles; Animals; Cellular biology; Child; Chronic; Cirrhosis; Clinical; Congenital Disorders; Data; Defect; Development; Disease; Drug toxicity; Embryo; Employee; Endoplasmic Reticulum; Etiology; Family; Fatty Liver; Fertilization; Fibrosis; Fishes; Functional disorder; Funding; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Hepatocyte; Hepatomegaly; Homeostasis; Hour; Human; Inborn Errors of Metabolism; International; Investigation; Larva; Link; Liver; Liver Dysfunction; Liver diseases; Manuscripts; Measures; Mediating; Metabolic syndrome; Modeling; Molecular Chaperones; Mus; Mutation; Obesity; Occupations; Organelles; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Protein Glycosylation; Protein Secretion; Proteins; Research; Role; Serum Proteins; Services; Stress; System; Testing; Time; Travel; United States National Institutes of Health; Vertebrates; Western Blotting; Work; Zebrafish; abstracting; alcohol exposure; alcohol response; combat; endoplasmic reticulum stress; glycosylation; improved; knock-down; liver function; liver transplantation; meetings; mutant; novel; protein folding; protein transport; response; symposium; time use; trafficking

Protein secretion is among· the most important functions of hepatocytes. Defects in the secretory pathway can have serious consequences~ For instance, patients with congenital disorders of glycosylation in which secreted proteins are not properly glycosylated and trafficked, have serious and multisystemic problems, including hepatic steatosis that a rapidly progresses to fibrosis requiring liver transplant in very young children. Additionally, stress in the secretory pathway, called ER stress, is associated with fatty liver disease resulting from obesity and alcohol abuse and is a new and exciting line of inquiry in this burgeoning field. Importantly, drugs that improve protein folding, which are currently in clinical use, are proposed as therapies for fatty liver disease (FLO). We are using zebrafish to study the mechanism by which defects in the secretory pathway, namely protein glycosylation and the unfolded protein response, contribute to FLO. We have developed 2 new models of COG in zebrafish. One of these is the foie gras (fgr) mutant, that we identified in an effort to identify vertebrate models of liver diseases through a forward genetic screen in zebrafish. fgr mutants develops steatosis. The fgr gene is recessive embryonic lethal and is well conserved in all animals, but has not been studied in any species other than zebrafish. The gene does not encode any sequence motifs that implicate a specific function or family, and thus it represents a potential novel player in FLO. Our recent data demonstrates an essential role for Fgr in protein N-glycosylation, and fgr mutants display features of COG. The first aim of this work is to characterize the fgr allele and to define the defects in organelle function and protein trafficking that occur as a result oUgr mutation. Our second aim is to investigate the link between the unfolded protein response and steatosis in our zebrafish models of COG and alcohol exposure. Using the power of zebrafish genetics, we will determine the role of each unfolded protein response branch in steatosis in fgr mutants and alcohol-treated fish. This will conclusively demonstrate whether this pathway is protective or pathologic in the development of steatosis.

蛋白质分泌是肝细胞最重要的功能之一。分泌途径的缺陷可能会产生严重的后果。例如，患有先天性糖基化疾病的患者，其中分泌的蛋白质没有被正确糖基化和运输，具有严重的多系统问题，包括肝脂肪变性，其在非常年幼的儿童中迅速发展为需要肝移植的纤维化。此外，分泌途径中的应激，称为ER应激，与肥胖和酒精滥用引起的脂肪肝有关，是这一新兴领域的一个新的令人兴奋的研究方向。重要的是，目前临床使用的改善蛋白质折叠的药物被提议作为脂肪肝疾病（FLO）的疗法。我们使用斑马鱼来研究分泌途径中的缺陷，即蛋白糖基化和未折叠蛋白反应，导致FLO的机制。我们在斑马鱼中开发了2种新的COG模型。其中之一是鹅肝酱（fgr）突变体，我们通过对斑马鱼的正向遗传筛选，努力确定肝脏疾病的脊椎动物模型。FGR突变体发生脂肪变性。fgr基因是隐性的胚胎致死基因，在所有动物中都很保守，但除了斑马鱼以外，还没有在任何物种中进行过研究。该基因不编码任何涉及特定功能或家族的序列基序，因此它代表了FLO中的潜在新参与者。我们最近的数据表明Fgr在蛋白质N-糖基化中的重要作用，并且fgr突变体显示COG的特征。这项工作的第一个目的是表征fgr等位基因，并定义作为oUgr突变的结果发生的细胞器功能和蛋白质运输的缺陷。我们的第二个目标是研究未折叠蛋白反应和脂肪变性之间的联系，在我们的斑马鱼模型的COG和酒精暴露。利用斑马鱼遗传学的力量，我们将确定fgr突变体和酒精处理的鱼脂肪变性中每个未折叠蛋白反应分支的作用。这将最终证明该途径在脂肪变性的发展中是保护性的还是病理性的。