Genome-wide ENU mutagenesis screen for Runx2 modifiers
Runx2 修饰符的全基因组 ENU 诱变筛选
基本信息
- 批准号:6956298
- 负责人:
- 金额:$ 9.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-08-01 至 2006-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The long-term goal of our project is to identify factors regulating mesenchymal cells commitment and early maturation into differentiated osteoblasts. As a first step toward this goal, we propose to perform a genome-wide genetic screen in mice using ethyl-nitrosourea (ENU) mutagenesis to expose mutations able to functionally compensate for Runx2 haploinsufficiency. Runx2 is the earliest known determinant of osteoblast differentiation, and loss of one Runx2 allele in mice or human causes Cleidocranial dysplasia (CCD), a skeletal disorder marked by clavicle agenesis and ossification defects. Any regulator of Runx2 expression or activity is thus likely to be involved in controlling either osteoblast differentiation or osteoblast function. Our strategy relies on a search for ENU-mutated animals that harbor a rescued CCD phenotype despite a Runx2 genetic background. We hypothesize that such rescuing mutations will affect regulators of Runx2 gene expression or protein stability/availability/activity or trigger yet unknown parallel or downstream compensating pathways. Subsequent characterization of the genes harboring these mutations should thus identify regulators involved in the early steps of skeletogenesis. The present application proposes to identify rescued Runx2 ENU mutants and to select the best candidates for subsequent mutation mapping and gene identification. Our specific aims are: to identify ENU-mutated mouse strains harboring a rescue of the CCD phenotype despite heterozygocity at the Runx2 locus; and to compare the mutant lines isolated and prioritize them for subsequent mutation mapping.
描述(由申请人提供):我们项目的长期目标是确定调节间充质细胞定向和早期成熟为分化成骨细胞的因素。作为实现这一目标的第一步,我们建议使用乙基亚硝基脲(ENU)诱变在小鼠中进行全基因组遗传筛选,以暴露能够在功能上补偿Runx 2单倍不足的突变。Runx 2是已知的最早的成骨细胞分化的决定因素,在小鼠或人类中丢失一个Runx 2等位基因会导致锁骨颅骨发育不良(CCD),这是一种以锁骨发育不全和骨化缺陷为标志的骨骼疾病。因此,Runx 2表达或活性的任何调节剂都可能参与控制成骨细胞分化或成骨细胞功能。我们的策略依赖于寻找ENU突变的动物,尽管有Runx 2遗传背景,但这些动物具有获救的CCD表型。我们假设这种拯救突变将影响Runx 2基因表达或蛋白质稳定性/可用性/活性的调节因子,或触发未知的平行或下游补偿途径。因此,随后对携带这些突变的基因进行表征,应该可以确定参与骨骼发生早期步骤的调节因子。本申请提出鉴定拯救的Runx 2 ENU突变体并选择最佳候选物用于随后的突变作图和基因鉴定。我们的具体目标是:鉴定尽管在Runx 2基因座处具有杂合性但仍具有CCD表型拯救的ENU突变的小鼠品系;并比较分离的突变品系并将它们优先用于随后的突变作图。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Patricia Florence Ducy其他文献
Patricia Florence Ducy的其他文献
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{{ truncateString('Patricia Florence Ducy', 18)}}的其他基金
Cross-talk between skeleton and pancreas morphogeneses during development
发育过程中骨骼和胰腺形态发生之间的串扰
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8806907 - 财政年份:2015
- 资助金额:
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Impact of gonadal failure on the bone-mediated regulation of glucose metabolism
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10417244 - 财政年份:2010
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Impact of gonadal failure on the bone-mediated regulation of glucose metabolism
性腺衰竭对骨介导的葡萄糖代谢调节的影响
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10024565 - 财政年份:2010
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Impact of gonadal failure on the bone-mediated regulation of glucose metabolism
性腺衰竭对骨介导的葡萄糖代谢调节的影响
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10254402 - 财政年份:2010
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Impact of gonadal failure on the bone-mediated regulation of glucose metabolism
性腺衰竭对骨介导的葡萄糖代谢调节的影响
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10632051 - 财政年份:2010
- 资助金额:
$ 9.75万 - 项目类别:
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