Identification of Mouse Airway Hyperresponsiveness Genes
小鼠气道高反应性基因的鉴定
基本信息
- 批准号:7312454
- 负责人:
- 金额:$ 44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-06-01 至 2010-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Airway hyperresponsiveness (AHR) is a component of asthma, and the complex inheritance of both asthma and AHR have made it difficult to find the genetic etiology of these important problems. Analysis in a less heterogeneous genetic system than the human population could be useful for identifying causal loci. We and others have attempted this using quantitative trait locus (QTL) analysis in the mouse, which provides an excellent model for naTve AHR, but the results of these studies have been inconsistent. As part of this Program, we have used a very different approach to address this. We created phenotypically selected recombinant congenic mice to identify loci associated with increased naTve AHR. The seventh generation hyperresponsive mice retained A/J loci on chromosomes 2, 6, and 10. Surprisingly, analysis of unselected N8 progeny demonstrated that the naive AHR phenotype was not significantly associated with any of the loci individually, but was highly significantly associated with an interaction of loci on chromosomes 2 and 6. These findings were confirmed in an independent analysis of consomic mice. Also, as part of the Program, we generated A/J mice that are genetically depleted of mast cells. These mice do not show naive AHR, demonstrating that this trait is mediated by mast cells. The identification of genomic regions containing loci causally associated with AHR, the
demonstration that this trait requires their interaction, and the observation that mast cells are required for expression of the disease phenotype has important implications for the dissection of the genetic etiology of asthma in humans. Of interest is that the protease ADAM33, which has been associated with the human disease by genetic analysis, is within the retained A/J region. An advantage of model systems is that they can facilitate functional analysis, and we propose to examine the role of ADAM33 using haplotype analysis and transgenesis. We also propose to further examine the role of mast cells in mediating the naive AHR observed in A/J mice by reciprocal bone marrow transplant and adoptive transfer. Lastly, we will continue to narrow the genetic interval in which the causal loci reside, with the aim of ultimately identifying the genes using a positional cloning strategy.
气道高反应性(AHR)是哮喘的一个组成部分,哮喘和AHR的复杂遗传性使得很难找到这些重要问题的遗传病因。在一个比人类群体异质性更小的遗传系统中进行分析可能有助于确定致病基因座。我们和其他人已经尝试在小鼠中使用数量性状基因座(QTL)分析,这为naTve AHR提供了一个很好的模型,但这些研究的结果不一致。作为该计划的一部分,我们使用了一种非常不同的方法来解决这个问题。我们创建了表型选择的重组同源小鼠,以鉴定与增加的naTve AHR相关的基因座。第七代高反应小鼠保留了染色体2、6和10上的A/J位点。令人惊讶的是,对BSN 8后代的分析表明,幼稚AHR表型与任何单独的基因座都不显著相关,但与染色体2和6上的基因座的相互作用高度显著相关。 这些发现在对consomic小鼠的独立分析中得到证实。此外,作为该计划的一部分,我们产生了遗传上耗尽肥大细胞的A/J小鼠。这些小鼠不显示幼稚AHR,表明该特征由肥大细胞介导。 鉴定含有与AHR因果相关的基因座的基因组区域,
证明这种特性需要它们之间的相互作用,并且观察到肥大细胞是疾病表型表达所必需的,这对人类哮喘遗传病因学的剖析具有重要意义。 令人感兴趣的是,通过遗传分析与人类疾病相关的蛋白酶ADAM 33在保留的A/J区域内。模型系统的一个优点是,它们可以促进功能分析,我们建议使用单倍型分析和转基因检查ADAM 33的作用。我们还建议进一步研究肥大细胞介导的幼稚AHR中观察到的相互骨髓移植和过继转移的A/J小鼠的作用。最后,我们将继续缩小致病基因座所在的遗传间隔,目的是最终使用定位克隆策略识别基因。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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DAVID R. BEIER其他文献
DAVID R. BEIER的其他文献
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{{ truncateString('DAVID R. BEIER', 18)}}的其他基金
Open-source Software Development Supplement for 3D quantitative analysisof mouse models of structural birth defects through computational anatomy
通过计算解剖学对结构性出生缺陷小鼠模型进行 3D 定量分析的开源软件开发补充
- 批准号:
10839199 - 财政年份:2023
- 资助金额:
$ 44万 - 项目类别:
Utilization of Advanced Technologies for the Understanding of Human Structural Birth Defects
利用先进技术了解人类结构性出生缺陷
- 批准号:
10327735 - 财政年份:2021
- 资助金额:
$ 44万 - 项目类别:
Utilization of Advanced Technologies for the Understanding of Human Structural Birth Defects
利用先进技术了解人类结构性出生缺陷
- 批准号:
10541184 - 财政年份:2021
- 资助金额:
$ 44万 - 项目类别:
Project I - Transcriptomic Analysis of Structural Birth Defects in Mouse Developmental Mutants
项目 I - 小鼠发育突变体结构性出生缺陷的转录组分析
- 批准号:
10154928 - 财政年份:2021
- 资助金额:
$ 44万 - 项目类别:
Project I - Transcriptomic Analysis of Structural Birth Defects in Mouse Developmental Mutants
项目 I - 小鼠发育突变体结构性出生缺陷的转录组分析
- 批准号:
10327737 - 财政年份:2021
- 资助金额:
$ 44万 - 项目类别:
Utilization of Advanced Technologies for the Understanding of Human Structural Birth Defects
利用先进技术了解人类结构性出生缺陷
- 批准号:
10154926 - 财政年份:2021
- 资助金额:
$ 44万 - 项目类别:
Project I - Transcriptomic Analysis of Structural Birth Defects in Mouse Developmental Mutants
项目 I - 小鼠发育突变体结构性出生缺陷的转录组分析
- 批准号:
10541189 - 财政年份:2021
- 资助金额:
$ 44万 - 项目类别:
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