The Genetic Basis of Cholestasis

胆汁淤积的遗传基础

基本信息

批准号：
7232418
负责人：
LAURA N BULL
金额：
$ 29.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-02-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232418
关键词：
A Mouse ASBT protein ATP phosphohydrolase Abbreviations Adult Age Alanine Transaminase Alkaline Phosphatase Alleles Alopecia Animal Model Arthrogryposis Aspartate Transaminase Benign recurrent intrahepatic cholestasis Bile Acids Bile fluid Binding Binding Proteins Biological Biological Assay Body Weight decreased Breeding Candidate Disease Gene Cholates Cholestasis Chromosome Mapping Complex Core Facility Couples Cystic Fibrosis DNA Data Data Analyses Development Disease Etiology Family Family member Fertility Functional disorder Gamma-glutamyl transferase Gene Expression Genes Genetic Genetic Heterogeneity Genetic Markers Genetic Predisposition to Disease Genome Genomics Genotype Goals Grant Health Hematocrit procedure Hemoglobin Homeostasis Homozygote Human Human Genome ILBP Ichthyoses Impairment Intestines Intrahepatic Cholestasis Joints Kidney Knock-out LDLR gene Lecithin Leukocytes Lipid Binding Liver Liver diseases Localized Maps Metabolism Modality Morbidity - disease rate Mus Mutant Strains Mice Mutation Normal Range Numbers Organic Anion Transporters Oxidoreductase Pathway interactions Patients Phenotype Phosphatidylethanolamine Phosphatidylserines Play Polygenic Traits Polymerase Chain Reaction Predisposition Progressive intrahepatic cholestasis Protein Export Pathway Proteins Quantitative Trait Loci RXR Research Personnel Resistance Role Sclerosing Cholangitis Severity of illness Steroid delta-isomerase Steroids Syndrome Taurodeoxycholate Thinking Tissues Vacuole Variant Vitamin D3 Receptor Weaning Weight base bile acid-CoA amino acid N-acyltransferase bile salts cholate constitutive androstane receptor day dietary supplements feeding genetic variant human NR0B2 protein human disease intrahepatic intrahepatic cholestasis of pregnancy member mortality mouse model mutant novel phosphatidylethanolamine pregnane X receptor programs pup receptor response trait

项目摘要

DESCRIPTION (provided by the applicant): Liver disease is a cause of substantial morbidity and mortality in the U.S. and cholestasis (impairment of bile flow) is a common and devastating manifestation of liver disease. This is an application to renew a grant focused on increasing our understanding of the biological causes of cholestasis, and more specifically, the role of the FIC1 (ATP8B1) protein in health and disease. Mutations in the gene encoding FIC1 (a P-type ATPase) have previously been identified as the genetic etiology of some cases of progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC). A mouse model of FIC1 disease has been generated and partially characterized, resulting in the novel finding that excessive bile salt resorption may contribute to development of cholestasis. The phenotype of Fic 1-deficient mice differs depending upon the murine strain background, indicating the existence of genetic modifiers of the murine Fic 1-deficient phenotype. Similarly, human patients who share the same FIC1 mutation can have widely varying severity of disease. Mapping and identification of modifier loci for the murine Fic 1-deficient phenotype will illuminate the biological role of FIC1, and may identify candidate susceptibility loci for development and progression of FIC1 disease, as well as more common disorders of complex etiology. This proposal focuses on use of genetic and candidate gene approaches to identification of modifier loci influencing strain-specific phenotypic differences, including weight at weaning, and response to bile salt supplemented diet, in Fic1 mutant mice. In Specific Aim 1, we will perform further phenotypic characterization of the Fic1 mutant mice in C57B1/6, 129S1, and 129S4 strain backgrounds. Results of these studies will inform Specific Aims 2-4. In Specific Aim 2, we will genetically map modifier loci for phenotypic traits of Fic1 mutant mice that differ between the C57B1/6 and 129 strains. In Specific Aim 3, we will use genetic, candidate gene, and other approaches to further characterize 3 of these loci, with the goal of identifying a strong candidate gene for one or more of the modifier loci. In Specific Aim 4, we will more precisely define the genomic regions thought to differ between the 129S1 and 129S4 strains, and perform targeted studies to correlate phenotypic and genotypic findings in Fic1 mutant mice of 129S1, 129S4, and mixed 129S1;129S4 strain backgrounds.

描述（由申请人提供）：肝病是美国的大量发病率和死亡率的原因，胆汁淤积（胆汁流量受损）是肝病的常见且毁灭性的表现。这是一种申请，重新授予了我们对胆汁淤积的生物学原因的理解，更具体地说，是FIC1（ATP8B1）蛋白在健康和疾病中的作用。编码FIC1（P型ATPase）的基因中的突变先前已被鉴定为某些进行性家族性家族性肝内胆汁淤积（PFIC）和良性复发性肝内胆汁淤积（BRIC）的遗传病因。已经产生并部分表征了FIC1疾病的小鼠模型，从而导致了新发现的发现，胆汁盐吸收过多可能有助于胆汁淤积的发展。 FIC 1缺陷小鼠的表型取决于鼠应变的背景，表明鼠FIC 1缺陷表型的遗传修饰符存在。同样，具有相同FIC1突变的人类患者的疾病严重程度可能很大。鼠FIC 1缺陷表型的修饰基因座的映射和鉴定将阐明FIC1的生物学作用，并可能识别候选易感性基因座用于FIC1疾病的发展和进展以及复杂病因的更常见疾病。该建议着重于使用遗传和候选基因方法来鉴定修饰基因座影响特异性表型差异，包括断奶时的体重，以及对FIC1突变小鼠中胆汁盐补充饮食的反应。在特定的目标1中，我们将在C57B1/6、129S1和129S4菌株背景中对FIC1突变小鼠进行进一步的表型表征。这些研究的结果将为特定目标2-4提供信息。在特定的目标2中，我们将在遗传学上绘制修饰剂基因座的FIC1突变小鼠的表型特征，这些特征在C57B1/6和129菌株之间有所不同。在特定的目标3中，我们将使用遗传，候选基因和其他方法进一步表征其中的3个基因座，目的是确定一个或多个修饰剂基因座的强候选基因。在特定目标4中，我们将更精确地定义129S1和129S4菌株之间被认为有所不同的基因组区域，并进行有针对性的研究，以将129S1、129S4和混合129S4菌株背景的FIC1突变小鼠的表型和基因型发现相关联。