Genetic control of hepatic fibrogenesis

肝纤维化的遗传控制

基本信息

  • 批准号:
    8152194
  • 负责人:
  • 金额:
    $ 17.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-09-30 至 2013-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Alcoholic and non-alcoholic fatty liver disease (NAFLD) are chronic liver disorders in which the liver progressively transitions from fatty accumulation and steatohepatitis (NASH) to fibrosis and cirrhosis. The mechanisms regulating this transition, despite significant interest and research efforts, are still largely unresolved. Our specific hypothesis is that the genetic variability created in the Collaborative Cross recombinant inbred 8-way intercross strains will allow the genetic factors regulating hepatic fibrogenesis to be identified. In other words, we hypothesize that fibrosis susceptibility results from the combined effects of genetic variations within genes termed "quantitative trait loci" (QTL). To address this important hypothesis, the newly developed Collaborative Cross strains will be used to establish phenotypes associated with fibrosis induced by carbon tetrachloride. The rationale for the use of the Collaborative Cross strains is that within nearly 100 substrains over 95% of genetic variability is captured and over 100,000 genetic recombination points are established, making ultra-fine QTL mapping of a phenotype more precise and significant. Also, because parental polymorphisms are uniformly dispersed throughout the Collaborative Cross lines, a uniform and continuous distribution of phenotypic responses is anticipated in the strains. Thus, this approach of linkage is far more superior and much more relevant to human biology than the traditional approaches using single-gene transgenic, knock-out strains or even recombinant inbred strains. The key objectives are to identify fibrosis-susceptible strains, characterize several fibrosis benchmark phenotypes across all strains, identify QTLs associated with the fibrosis phenotypes and exploit susceptible strains in a chronic model of ethanol exposure. The following aims are outlined to highlight these objectives. The goal of Specific Aim 1 is to identify fibrosis-susceptible strains and characterize phenotypic traits associated with fibrogenesis across 120 strains of the Collaborative Cross. Then, in Specific Aim2, we will genetically map quantitative traits associated with liver fibrogenesis to QTLs based on the CC genotypes. Finally, in Specific Aim 3, we will utilize fibrosis-prone strains identified above in a chronic model of ethanol exposure to determine ethanol-induced fibrosis susceptibility in these strains. These studies will be the springboard of ongoing studies which will allow for the identification and evaluation of candidate genes, pathways, and systems involved in the role of hepatic fat accumulation in the transition to liver fibrosis, an area with particular relevance to the evolution of metabolic syndrome, obesity, diabetes, and even cardiovascular disease. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic liver disease is a continuum of pathologies starting with fatty liver disease to steatohepatitis to fibrosis to cirrhosis. The mechanisms governing the transition to fibrosis are not well understood. We will use a novel genetically-defined mouse population derived from an 8-way intercross of common inbred strains called the Collaborative Cross in order to address the complex genetic factors that underlie the mechanisms of liver fibrosis. The outcome of this study is the identification of novel fibrosis-susceptible strains of mice that will be a valuable research tool but also the identification of genetic markers (quantitative trait loci) that are associated with fibrosis.
描述(由申请人提供):酒精性和非酒精性脂肪肝病(NAFLD)是慢性肝脏疾病,其中肝脏逐渐从脂肪堆积和脂肪性肝炎(NASH)转变为纤维化和肝硬化。尽管人们对此产生了浓厚的兴趣并进行了研究努力,但调节这种转变的机制在很大程度上仍未得到解决。我们的具体假设是,协作杂交重组近交8路交叉菌株中产生的遗传变异将允许鉴定调节肝纤维发生的遗传因素。换句话说,我们假设纤维化易感性是由称为“数量性状基因座”(QTL) 的基因内遗传变异的综合影响造成的。为了解决这一重要假设,新开发的协作杂交菌株将用于建立与四氯化碳诱导的纤维化相关的表型。使用协同杂交品系的理由是,在近100个亚品系中,捕获了超过95%的遗传变异,并建立了超过100,000个遗传重组点,使得表型的超精细QTL定位更加精确和重要。此外,由于亲本多态性均匀地分散在整个协作交叉系中,因此预计菌株中表型反应的均匀且连续的分布。因此,这种连接方法比使用单基因转基因、敲除菌株甚至重组近交菌株的传统方法更加优越,并且与人类生物学更加相关。主要目标是识别纤维化敏感菌株,表征所有菌株的几种纤维化基准表型,识别与纤维化表型相关的 QTL,并在慢性乙醇暴露模型中利用敏感菌株。概述了以下目标以突出这些目标。具体目标 1 的目标是鉴定纤维化敏感菌株,并表征与协作杂交的 120 个菌株中的纤维发生相关的表型特征。然后,在Specific Aim2中,我们将根据CC基因型,将与肝纤维发生相关的数量性状基因映射到QTL。最后,在具体目标 3 中,我们将在乙醇暴露的慢性模型中利用上面确定的易纤维化菌株来确定这些菌株中乙醇诱导的纤维化易感性。这些研究将成为正在进行的研究的跳板,这些研究将允许识别和评估参与肝脂肪积累在肝纤维化转变过程中的作用的候选基因、途径和系统,肝纤维化是一个与代谢进化特别相关的领域。综合征、肥胖、糖尿病,甚至心血管疾病。 公共卫生相关性:项目叙述慢性肝病是从脂肪肝病到脂肪性肝炎到纤维化再到肝硬化的一系列病理过程。控制向纤维化转变的机制尚不清楚。我们将使用一种新型的基因定义的小鼠群体,该群体源自常见近交系的 8 路杂交,称为“协作杂交”,以解决肝纤维化机制背后的复杂遗传因素。这项研究的结果是鉴定出新型的纤维化易感小鼠品系,这将是一个有价值的研究工具,同时也鉴定出与纤维化相关的遗传标记(数量性状位点)。

项目成果

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MICHAEL D WHEELER其他文献

MICHAEL D WHEELER的其他文献

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{{ truncateString('MICHAEL D WHEELER', 18)}}的其他基金

B12 Regulation of PUFA Synthesis
B12 PUFA 合成的调控
  • 批准号:
    10042751
  • 财政年份:
    2020
  • 资助金额:
    $ 17.13万
  • 项目类别:
B12 Regulation of PUFA Synthesis
B12 PUFA 合成的调控
  • 批准号:
    10263940
  • 财政年份:
    2020
  • 资助金额:
    $ 17.13万
  • 项目类别:
Genetic control of hepatic fibrogenesis
肝纤维化的遗传控制
  • 批准号:
    8048297
  • 财政年份:
    2010
  • 资助金额:
    $ 17.13万
  • 项目类别:
Genetic control of hepatic fibrogenesis
肝纤维化的遗传控制
  • 批准号:
    8048297
  • 财政年份:
    2010
  • 资助金额:
    $ 17.13万
  • 项目类别:
Hepatic lymphocytes and fatty liver disease
肝淋巴细胞与脂肪肝
  • 批准号:
    7880474
  • 财政年份:
    2010
  • 资助金额:
    $ 17.13万
  • 项目类别:
Acute Ethanol-Induced Innate Immune Response in Liver
急性乙醇诱导的肝脏先天免疫反应
  • 批准号:
    6878118
  • 财政年份:
    2003
  • 资助金额:
    $ 17.13万
  • 项目类别:
Acute Ethanol-Induced Innate Immune Response in Liver
急性乙醇诱导的肝脏先天免疫反应
  • 批准号:
    6599813
  • 财政年份:
    2003
  • 资助金额:
    $ 17.13万
  • 项目类别:
Acute Ethanol-Induced Innate Immune Response in Liver
急性乙醇诱导的肝脏先天免疫反应
  • 批准号:
    6729993
  • 财政年份:
    2003
  • 资助金额:
    $ 17.13万
  • 项目类别:
Cell type gene delivery and alcoholic liver disease
细胞类型基因传递和酒精性肝病
  • 批准号:
    6751869
  • 财政年份:
    2002
  • 资助金额:
    $ 17.13万
  • 项目类别:
Cell type gene delivery and alcoholic liver disease
细胞类型基因传递和酒精性肝病
  • 批准号:
    6894796
  • 财政年份:
    2002
  • 资助金额:
    $ 17.13万
  • 项目类别:

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揭示 GPR75 作为脂肪酸转运蛋白激活剂在非酒精性脂肪性肝病 (NAFLD) 中的作用
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