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

基本信息

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
项目类别：
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

项目摘要

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。脂肪变性会迅速发展为纤维化，需要在幼儿中进行肝移植。此外，分泌途径中的压力（称为内质网压力）与肥胖和酗酒引起的脂肪肝疾病有关。重要的是，目前临床上使用的改善蛋白质折叠的药物被提议作为脂肪肝疾病（FLO）的治疗方法。分泌途径的缺陷，即蛋白质糖基化和未折叠的蛋白质反应，导致了 FLO。我们在斑马鱼中开发了两种新的 COG 模型，其中之一是鹅肝 (fgr) 突变体。通过正向遗传筛选，在斑马鱼中发现了导致脂肪变性的脊椎动物肝脏疾病模型。 fgr 基因是隐性胚胎致死基因，在所有动物中都得到了很好的保存，但尚未在斑马鱼以外的任何物种中进行过研究。该基因不编码任何暗示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，我们最近的数据证明了 Fgr 在蛋白质中的重要作用。 N-糖基化和 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，并确定 oUgr 突变导致的细胞器功能和蛋白质运输缺陷。在我们的 COG 和酒精暴露斑马鱼模型中，未折叠蛋白反应与脂肪变性之间的联系，利用斑马鱼遗传学的力量，我们将确定每个未折叠蛋白反应分支在脂肪变性中的作用。 fgr 突变体和酒精处理的鱼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。