Genetics of Nonalcoholic Fatty Liver Disease (NAFLD)

非酒精性脂肪肝 (NAFLD) 的遗传学

• 批准号: 8056146
• 负责人: Sandra Karolyn Erickson
• 金额: $ 30.28万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056146
• 关键词: 129 Mouse; Address; Adult; Animal Model; Atherosclerosis; Bioinformatics; Breeding; Candidate Disease Gene; Chronic Disease; Complex; Coupled; Development; Diagnostic; Diet; Environmental Risk Factor; Etiology; Fatty Liver; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Human; Human Development; Human Genome; Inbreeding; Incidence; Individual; Knowledge; Lead; Link; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Metabolic Diseases; Microarray Analysis; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligonucleotide Microarrays; Overweight; Phenotype; Population; Populations at Risk; Predisposition; Prevention; Prevention strategy; Primary carcinoma of the liver cells; Public Health; Quantitative Trait Loci; Risk Factors; Steatohepatitis; Translations; Variant; Work; base; design; feeding; genome-wide; human disease; liver transplantation; non-alcoholic fatty liver; nonalcoholic steatohepatitis; prognostic; response; therapy development; trait; treatment strategy

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is an increasingly important public health problem world-wide. It is conservatively estimated that -25% of the general US population has NAFLD. -25% of such individuals may develop steatohepatitis (NASH) and as many as 3% of these ultimately may require liver transplant. Development of NAFLD and its progression to chronic disease appears to be multifactorial and is poorly understood in the vast majority of individuals. Based on evidence to date, genetic predisposition coupled with environmental factors, such as diet, are involved. Our long term goal is to identify genes involved in the development and progression of NAFLD. We discovered that mixed genetic background (129;B6) mice spontaneously developed the entire spectrum of NAFLD when fed a Western diet. In preliminary studies of the two parental strains, 129 mice developed NASH by 15 weeks, but B6 mice developed a mild steatosis only. These results allow us to propose the following two independent specific aims: Specific Aim 1: To determine chromosomal regions that confer susceptibility to Western diet-induced NAFLD by quantitative trait locus (QTL) analyses of F2 generation mice derived from parental mouse strains 129S1/SvlmJ (129) and C57BI/6J (B6). a. To phenotype for NAFLD-related traits and to genotype F2 generation mice fed the Western diet. b. To use bioinformatic analyses to determine NAFLD-associated QTLs, including linked and epistatic. Specific Aim 2: To assess innate differences in 129 and B6 parental mouse strains and their F1 progeny. a. To determine genome-wide gene expression differences between parental strains using replicated oligonucleotide microarray analysis. b. To determine dominance of NAFLD phenotypic traits using a F1 generation breeding strategy. The major goal of the proposed work is to discover chromosomal regions and genes that confer susceptibility to the entire spectrum of NAFLD. Knowledge of the genetic factors that influence development of NAFLD and its progression would lead to development of rational prevention and treatment strategies, including design of specific gene-targeted pharmacological interventions, development of prognostic or diagnostic indicators and would enable identification of at risk populations and individualization of therapies.

描述（由申请人提供）：非酒精性脂肪肝疾病（NAFLD）是全球越来越重要的公共卫生问题。保守地估计，美国普通人群的-25％具有NAFLD。 -25％的人可能患有脂肪性肝炎（NASH），其中多达3％的最终可能需要肝移植。 NAFLD的发展及其向慢性疾病的发展似乎是多因素的，并且在绝大多数个体中对此却很少理解。根据迄今为止的证据，涉及遗传易感性以及饮食等环境因素。我们的长期目标是确定与NAFLD发展和发展有关的基因。我们发现，混合遗传背景（129; b6）小鼠在喂西方饮食时会自发发展NAFLD的整个光谱。在两种亲本菌株的初步研究中，129只小鼠在15周内出​​现了NASH，但B6小鼠仅出现轻度的脂肪变性。这些结果使我们能够提出以下两个独立的特定目的：具体目标1：确定染色体区域通过定量性状基因座（QTL）分析源自雌科生小鼠菌株129S1/svlmj（129）和C57BI/6J（B6）的F2产生小鼠的染色体区域。一个。与NAFLD相关性状的表型和喂食西方饮食的基因型F2代生成小鼠。 b。使用生物信息学分析来确定与NAFLD相关的QTL，包括链接和上毒。特定目的2：评估129和B6父母菌株及其F1后代的先天差异。一个。使用复制的寡核苷酸微阵列分析，确定范围全基因组基因表达差异。 b。使用F1代生成策略来确定NAFLD表型性状的优势。拟议工作的主要目标是发现染色体区域和基因赋予整个NAFLD范围的敏感性。了解影响NAFLD发展及其进展的遗传因素将导致理性预防和治疗策略的发展，包括设计特定基因靶向的药理干预措施，预后或诊断指标的发展，并能够鉴定出在风险种群中的识别和疗法的个性化。

项目成果

Profiling sterols in cerebrotendinous xanthomatosis: utility of Girard derivatization and high resolution exact mass LC-ESI-MS(n) analysis.

• DOI: 10.1016/j.jchromb.2010.11.019
• 发表时间: 2011-05-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: DeBarber, Andrea E.;Sandlers, Yana;Pappu, Anuradha S.;Merkens, Louise S.;Duell, P. Barton;Lear, Steven R.;Erickson, Sandra K.;Steiner, Robert D.
• 通讯作者: Steiner, Robert D.