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）：非酒精性脂肪肝病（NAFLD）是世界范围内日益重要的公共卫生问题。据保守估计，美国总人口中 -25% 患有 NAFLD。 -25% 的此类个体可能会患上脂肪性肝炎 (NASH)，其中多达 3% 的人最终可能需要肝移植。 NAFLD 的发展及其向慢性疾病的进展似乎是多因素影响的，并且绝大多数人对此知之甚少。根据迄今为止的证据，遗传倾向与饮食等环境因素相结合。我们的长期目标是确定参与 NAFLD 发生和进展的基因。我们发现，混合遗传背景 (129;B6) 小鼠在喂食西方饮食时会自发患上全谱 NAFLD。在对两个亲本品系的初步研究中，129 只小鼠在 15 周时出现 NASH，但 B6 小鼠仅出现轻度脂肪变性。这些结果使我们能够提出以下两个独立的具体目标： 具体目标 1：通过对源自亲本小鼠品系 129S1/SvlmJ 的 F2 代小鼠进行数量性状位点 (QTL) 分析，确定对西方饮食诱导的 NAFLD 易感性的染色体区域(129) 和 C57BI/6J (B6)。一个。对 NAFLD 相关性状进行表型分析，并对饲喂西方饮食的 F2 代小鼠进行基因分型。 b.使用生物信息学分析确定 NAFLD 相关 QTL，包括连锁 QTL 和上位 QTL。具体目标 2：评估 129 和 B6 亲本小鼠品系及其 F1 后代的先天差异。一个。使用复制寡核苷酸微阵列分析确定亲本菌株之间的全基因组基因表达差异。 b.使用 F1 代育种策略确定 NAFLD 表型性状的优势。这项工作的主要目标是发现对整个 NAFLD 谱系易感性的染色体区域和基因。了解影响 NAFLD 发生及其进展的遗传因素将有助于制定合理的预防和治疗策略，包括设计特定基因靶向的药理学干预措施、制定预后或诊断指标，并有助于识别高危人群和个体化治疗的疗法。

项目成果

Nonalcoholic fatty liver disease.

非酒精性脂肪肝。

• DOI: 10.1056/nejm200209053471018
• 发表时间: 1986-09-13
• 期刊: Progress in liver diseases
• 作者: F. Schaffner;H. Thaler
• 通讯作者: H. Thaler

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

脑腱黄瘤病中甾醇的分析：吉拉德衍生化和高分辨率精确质量 LC-ESI-MS(n) 分析的实用性。

• 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
• 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.