Genetic Modifiers of Genome Instability & Cancer in Mice
基因组不稳定性的遗传修饰剂
基本信息
- 批准号:6990376
- 负责人:
- 金额:$ 14.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-05-06 至 2009-02-28
- 项目状态:已结题
- 来源:
- 关键词:DNA directed DNA polymeraseDNA repairDNA replicationWerner&aposs syndromecarcinogenesiscytogeneticsflow cytometrygene mutationgene rearrangementgenetic modelsgenetic susceptibilitygenetically modified animalsgenotypehelicaselaboratory mouseloss of heterozygositymodel design /developmentmolecular pathologyneoplasm /cancer geneticsphenotypeprotein structure function
项目摘要
A Wrn "knockout" mouse (Wrn delta) was recently generated that eliminates WRN protein expression (similar to Werner Syndrome) but fails to impart a significant phenotype. This suggests that functional redundancies in mice mask the Wrn4 phenotype. The objective
of this project is to characterize potential genetic modifiers of Wrn that affect genome instability and cancer in Wrn delta mice. The SPECIFIC AIMS are:
1. Determine the effect of genetic background on cancer development in Wrn delta mice. We will fast test the hypothesis that genetic background modifies the phenotype of Wrn delta mice. Our approach will be to introduce the Wrn delta allele into congenic inbred strains with different inherent cancer phenotypes, An extensive analysis of Wrn delta in different inbred strains will determine the relative contributions of genetic background and the Wrn delta allele to tissue-specific cancer risk.
2. Examine functional interactions of Wrn with Blm, Atm and Msh2. Studies in yeast show that parallel redundant pathways are often employed to preserve genome stability. A subset of these require the WRN homolog, SGS1. Accordingly, when sgs1 null mutations are combined with defects in parallel pathways, synergistic increases in spontaneous gross chromosomal
rearrangements (GCRs) are observed. Using available knockout mouse strains, we will examine three mutants that are predicted to synergize with Wrn delta: Blm delta, Atm delta and Msh2 delta.
3. Determine the effect of DNA polymerase errors in Wrn delta mice. RecQ helicases are closely linked to replicative DNA polymerases (SGS1 is epistatic with DNA polymerase epsilon; WRN binds DNA polymerase delta), and it is hypothesized that spontaneous GCRs result, in large part, from DNA replication errors. This suggests that error-prone DNA replication wilt amplify the Wrn delta phenotype. We will test this idea by crossing Wrn delta mice with two "mutator" mouse lines recently generated in our laboratory that are defective for Pol delta or Pol epsilon proofreading.
Together, these experiments will reveal Wrn functional interactions that affect genome instability and cancer in mice. Our long-term goal is to develop a meuse model that recapitulates fundamental aspects of the Werner Syndrome cancer phenotype, These studies will be integrated with the Cell Function-Monnat and Recombination Mechanisms-Maizels projects to develop a detailed molecular and organismal description of WNR function in rive. Our studies will also lay the ground work for a collaboration with the first project (Biochemistry-Loeb) evaluating Wrn Exo-, Hel- and SNP "knockin" mice.
最近产生了一种WRN“敲除”小鼠(WRN delta),其消除了WRN蛋白表达(类似于Werner综合征),但未能赋予显著的表型。这表明小鼠中的功能冗余掩盖了cDNA 4表型。客观
该项目的主要目的是描述影响基因组不稳定性和癌症的潜在的BDN基因修饰剂。具体目标是:
1.确定遗传背景对C18小鼠癌症发展的影响。我们将快速检验遗传背景改变了C18 n δ小鼠表型的假设。我们的方法是将Wrn delta等位基因引入具有不同固有癌症表型的同类近交系中,对不同近交系中Wrn delta的广泛分析将确定遗传背景和Wrn delta等位基因对组织特异性癌症风险的相对贡献。
2.检查BLN与Blm、Atm和Msh 2的功能相互作用。在酵母中的研究表明,平行的冗余途径经常被用来保持基因组的稳定性。其中的一个子集需要WRN同源物SGS 1。因此,当sgs 1无效突变与平行通路中的缺陷结合时,自发性总染色体数目的协同增加,
观察到重排(GCR)。使用可用的基因敲除小鼠品系,我们将检查预测与Msh 2 δ协同作用的三种突变体:Blm δ、Atm δ和Msh 2 δ。
3.确定DNA聚合酶错误对小鼠的影响。RecQ解旋酶与复制型DNA聚合酶密切相关(SGS 1与DNA聚合酶β具有上位性; WRN结合DNA聚合酶δ),并且假设自发GCR在很大程度上是由DNA复制错误引起的。这表明,易错DNA复制将放大Δ cDNA-delta表型。我们将测试这个想法,通过交叉的pol delta小鼠与两个“突变”小鼠系最近在我们的实验室,是有缺陷的Pol delta或Pol delta校对。
总之,这些实验将揭示影响小鼠基因组不稳定性和癌症的基因功能相互作用。我们的长期目标是开发一个默兹模型,概括Werner综合征癌症表型的基本方面,这些研究将与细胞功能-Monnat和增殖机制-Maizels项目相结合,以开发一个详细的分子和生物学描述WNR功能在rive。我们的研究还将为与第一个项目(Biochemistry-Loeb)合作评估Aprixin Exo-,Hel-和SNP“敲入”小鼠奠定基础。
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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BRADLEY D PRESTON其他文献
BRADLEY D PRESTON的其他文献
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{{ truncateString('BRADLEY D PRESTON', 18)}}的其他基金
Pol Epsilon Proofreading and Genetic Stability in Mice
Pol Epsilon 校对和小鼠遗传稳定性
- 批准号:
7035141 - 财政年份:2006
- 资助金额:
$ 14.35万 - 项目类别:
Pol Epsilon Proofreading and Genetic Stability in Mice
Pol Epsilon 校对和小鼠遗传稳定性
- 批准号:
7214068 - 财政年份:2006
- 资助金额:
$ 14.35万 - 项目类别:
Pol Epsilon Proofreading and Genetic Stability in Mice
Pol Epsilon 校对和小鼠遗传稳定性
- 批准号:
7369794 - 财政年份:2006
- 资助金额:
$ 14.35万 - 项目类别:
Pol Epsilon Proofreading and Genetic Stability in Mice
Pol Epsilon 校对和小鼠遗传稳定性
- 批准号:
7572941 - 财政年份:2006
- 资助金额:
$ 14.35万 - 项目类别:
MUTATOR ALLELES OF DNA POLYMERASE DELTA
DNA 聚合酶 Delta 的突变等位基因
- 批准号:
6628627 - 财政年份:2000
- 资助金额:
$ 14.35万 - 项目类别:
MUTATOR ALLELES OF DNA POLYMERASE DELTA
DNA 聚合酶 Delta 的突变等位基因
- 批准号:
6042672 - 财政年份:2000
- 资助金额:
$ 14.35万 - 项目类别:
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