Cloning a major gene for mouse adenovirus susceptibility

小鼠腺病毒易感性主基因的克隆

• 批准号: 7545496
• 负责人: Katherine R. Spindler
• 金额: $ 35.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545496
• 关键词: Acute Pneumonia; Adenovirus Infections; Adenoviruses; Alleles; Antiviral Agents; BALB/cJ Mouse; Backcrossings; Biological; Bone Marrow Transplantation; Brain; Candidate Disease Gene; Cessation of life; Child; Childhood; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 15; Cloning; Communicable Diseases; Congenic Strain; Developed Countries; Developing Countries; Disease; Disease susceptibility; Equilibrium; Exons; Gene Components; Gene Expression; Generations; Genes; Genetic; Genetic Epistasis; Genome; Genotype; Goals; Haplotypes; Immune; Immune response; Immune system; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Infection; Integration Host Factors; Introns; Life; Link; Maps; Minor; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Play; Polymorphic Microsatellite Marker; Positioning Attribute; Predisposition; Quantitative Trait Loci; Recombinants; Recruitment Activity; Research; Research Personnel; Resistance; Resolution; Risk; Role; SJL/J Mouse; Single Nucleotide Polymorphism Map; Spleen; Study models; Susceptibility Gene; System; Testing; Tissues; Transgenes; Transgenic Mice; Transplant Recipients; Viral; Virus; Virus Diseases; base; bone; density; design; gene interaction; gene therapy; genetic linkage analysis; mortality; pathogen; programs; resistant strain; respiratory; tool; tumorigenesis; virus host interaction

Adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries, where they are a major cause of illness and death. 5-15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50-80%. However, little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Identification of such host factors will enable better design of antiviral and immune suppressive therapy and adenovirus-based gene therapy. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease, because it can be studied in the natural host and there are inbred strains with different susceptibilities to MAV-1. The objective of this proposal is to define and characterize the host gene(s) underlying a major quantitative trait locus (QTL) for MAV-1 susceptibility in inbred mice. The central hypothesis is that the major QTL on Chromosome 15 for MAV-1 susceptibility in SJL/J mice contains an immune system gene that is polymorphic in susceptible and resistant mice. Genetic mapping will be combined with candidate gene approaches in two specific aims. (1) The major QTL for susceptibility will be fine mapped using several complementary approaches. A high density of polymorphic markers will be used to genotype recombinant progeny backcross, intercross, and third-generation cross mice (recombinant progeny testing). An interval-specific congenic strain will be constructed in which the interval from susceptible SJL/J mice will be introgressed into the resistant BALB/cJ background. Additional inbred mouse strains will be tested to determine whether they share a genetic basis for susceptibility with the major QTL in SJL/J mice. If so they will be used for fine mapping, haplotype analysis, and candidate gene identification. (2) A list of 20-30 candidate genes for the Chromosome 15 QTL will be compared for sequence and gene expression differences between susceptible and resistant strains. A candidate gene will be identified and tested genetically by replacing it in a resistant strain with the susceptible allele. The project is expected to identify a previously undescribed int¿ractiorT^ieT^eerrK6sfiTrTrmrne res immune evasion, thus increasing our understanding of viral infections and mechanisms of host response to pathogens. ~

腺病毒引起5-10%的儿童呼吸道疾病， 在发展中国家，儿童是疾病和死亡的主要原因。5-15%的儿童骨 骨髓移植患者发生腺病毒感染;发病率为50- 80%。然而， 了解腺病毒的发病机制，特别是宿主因素对疾病易感性的贡献。 鉴定这些宿主因子将能够更好地设计抗病毒和免疫抑制治疗， 基于腺病毒的基因治疗。小鼠腺病毒1型（MAV-1）提供了一个很好的模型， 研究对传染病的易感性，因为它可以在自然宿主中进行研究， 对MAV-1具有不同亲和性的近交系。本建议的目的是界定和 表征MAV-1易感性的主要数量性状基因座（QTL）的宿主基因， 近交系小鼠中心假设是，MAV-1易感性的15号染色体上的主要QTL是MAV-1抗性基因。 SJL/J小鼠含有免疫系统基因，该基因在易感小鼠和抗性小鼠中是多态性的。遗传 将在两个具体目标中将绘图与候选基因方法相结合。(1)主效QTL 将使用几种互补的方法对敏感性进行精细绘图。高密度的多态性 将使用标记对重组后代回交、互交和第三代杂交进行基因分型 小鼠（重组后代测试）。将构建间隔特异性同源菌株，其中 将来自易感SJL/J小鼠的间隔基因渗入到抗性BALB/cJ背景中。额外 将对近交系小鼠品系进行测试，以确定它们是否与 SJL/J小鼠的主要QTL。如果是这样，它们将用于精细定位，单倍型分析和候选基因 识别. (2)将比较15号染色体QTL的20-30个候选基因的列表， 敏感株和抗性株之间的序列和基因表达差异。候选基因将 通过在抗性品系中用易感等位基因替换它来进行鉴定和遗传测试。项目 预计将确定一种以前未描述的干扰物， 免疫逃避，从而增加了我们对病毒感染和宿主反应机制的理解。 病原体~