Identification of Loci Modifying Atm Lymphomagenesis

Atm 淋巴瘤发生基因座的鉴定

• 批准号: 9294021
• 负责人: Michael M. Weil
• 金额: $ 34.35万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-13 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294021
• 关键词: ATM gene; Age of Onset; Alleles; Analysis of Variance; Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Patients; Atlas of Cancer Mortality in the United States; Bioinformatics; Breeding; Candidate Disease Gene; Clinical; Congenic Strain; Development; Event; Experimental Designs; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Genome; Genotype; Germ-Line Mutation; Goals; Hematologic Neoplasms; Heritability; Homologous Gene; Human; Human Characteristics; Hybrids; Inbred Strains Mice; Incidence; Individual; Knock-out; Knockout Mice; Lead; Loss of Heterozygosity; Lymphoid Cell; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Maps; Measures; Methods; Modeling; Molecular; Molecular Analysis; Monitor; Mus; Mutation; Neurodegenerative Disorders; Pathway interactions; Patients; Penetrance; Phenotype; Play; Positioning Attribute; Predisposition; Public Health; Quantitative Trait Loci; Research; Resolution; Risk; Role; Single Nucleotide Polymorphism; Syndrome; Thymic Lymphoma; Untranslated RNA; Variant; analytical method; analytical tool; ataxia telangiectasia mutated protein; base; density; experimental study; genome-wide; high risk; improved; individual patient; leukemia; leukemia/lymphoma; mouse model; novel; novel strategies; phenotypic data; prevent; public health relevance

 DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a heritable syndrome associated with a high risk for leukemia and lymphoma. The syndrome arises in individuals with two defective copies of the ATM gene, but whether a specific A-T patient develops leukemia or lymphoma appears to be controlled not by their ATM mutation(s), but by unknown modifier genes. In the Atm knockout mouse model of A-T, lymphoma incidence and latency depend on the inbred mouse strain carrying the Atm knockout alleles, which is further evidence that modifier genes control leukemia/lymphoma latency and incidence. Our long term objective is to identify these modifier genes in mice and determine if their human homologues play a role in leukemia or lymphoma susceptibility in A-T patients or in patients with sporadic hematological malignancies. The specific aims of this proposal are to map the modifier genes in the mouse A-T model at high resolution (between 20 kb and 2 Mb) and then rank the genetic polymorphisms in the mapped regions according to their likely roles in lymphomagenesis. The mapping will be accomplished using a novel approach which combines the high mapping resolution of murine heterogeneous stocks with the use of a genetically modified allele. The Atm knockout allele will be introgressed into HS/Npt heterogeneous stock mice through two breeding generations. Mice homozygous for the knockout allele will be monitored for lymphoma development and latency, and genotyped for about 78,000 SNPs. Loci controlling lymphoma susceptibility and latency will be identified using an analysis of molecular variance approach modified to account for the breeding strategy needed to introduce the knockout allele. Genes in the mapped regions that are likely to be involved in lymphomagenesis will be identified using bioinformatics approaches and the effects of sequence variations within these genes will be assessed by gene expression studies in lymphoid cells and loss of heterozygosity studies in lymphomas.

 描述（由申请人提供）：共济失调-毛细血管扩张（A-T）是一种与白血病和淋巴瘤高风险相关的遗传性综合征。该综合征出现在具有两个缺陷ATM基因拷贝的个体中，但是特定A-T患者是否发展白血病或淋巴瘤似乎不是由其ATM突变控制，而是由未知的修饰基因控制。在A-T的Atm敲除小鼠模型中，淋巴瘤的发病率和潜伏期取决于携带Atm敲除等位基因的近交系小鼠品系，这进一步证明了修饰基因控制白血病/淋巴瘤的潜伏期和发病率。我们的长期目标是在小鼠中鉴定这些修饰基因，并确定它们的人类同源物是否在A-T患者或散发性恶性血液病患者的白血病或淋巴瘤易感性中发挥作用。该建议的具体目标是以高分辨率（20 kb和2 Mb之间）绘制小鼠A-T模型中的修饰基因，然后根据其在淋巴瘤发生中的可能作用对绘制区域中的遗传多态性进行排名。将使用一种新的方法完成映射，该方法将鼠异质性原种的高映射分辨率与遗传修饰等位基因的使用相结合。Atm基因敲除等位基因将通过两代繁殖渗入HS/Npt异种原种小鼠中。将监测敲除等位基因的纯合小鼠的淋巴瘤发展和潜伏期，并对约78，000个SNP进行基因分型。控制淋巴瘤易感性和潜伏期的基因座将使用经修改的分子方差分析方法来鉴定，以解释引入敲除等位基因所需的育种策略。将使用生物信息学方法鉴定可能参与淋巴瘤发生的映射区域中的基因，并通过淋巴细胞中的基因表达研究和淋巴瘤中杂合性丢失研究评估这些基因内序列变异的影响。