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（由适用提供）：共济失调 - 塞氏司法症（A-T）是一种可遗传的综合征，与白血病和淋巴瘤的高风险相关。该综合征在具有两个ATM基因的两个有缺陷的个体中出现，但是特定的A-T患者发展性白血病还是淋巴瘤似乎不是由其ATM突变而是由未知的修饰剂基因控制。在A-T的ATM基因敲除小鼠模型中，淋巴瘤的发病率和潜伏期取决于带有ATM基因敲除等位基因的近交小鼠应变，这进一步证明了修饰基因控制白血病/淋巴瘤潜伏期和发病率。我们的长期目标是鉴定小鼠中的这些修饰基因，并确定其人类同源物在A-T患者中或零星血液学恶性肿瘤患者中是否在白血病或淋巴瘤易感性中起作用。该建议的具体目的是映射修饰符基因。在小鼠A-T模型中，高分辨率（在20 kb和2 Mb之间），然后根据映射区域的遗传多态性对其在淋巴细胞化中的可能作用进行排名。将使用一种新型方法来完成映射，该方法结合了鼠异质库存的高映射分辨率与使用转基因等位基因的高映射分辨率。 ATM基因敲除等位基因将通过两个繁殖世代浸入HS/NPT异质库存小鼠中。纯合等位基因的纯合小鼠将受到淋巴瘤发育和潜伏期的监测，并分型为78,000个SNP。将通过对分子方差方法的分析来确定控制淋巴瘤易感性和潜伏期的基因座，以说明引入基因敲除等位基因所需的繁殖策略。将使用生物信息学方法来鉴定可能与淋巴细胞增多症有关的映射区域中的基因，这些基因内序列变化的影响将通过基因表达研究在淋巴样细胞中的基因表达研究以及淋巴瘤中杂合性研究的丧失来评估。