Cloning a major gene for mouse adenovirus susceptibility

克隆小鼠腺病毒易感性主要基因

• 批准号: 7331460
• 负责人: Katherine R. Spindler
• 金额: $ 35.18万
• 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/7331460
• 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; Range; 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; 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. ~

腺病毒导致儿童呼吸道疾病的5%-10%，并与#年的急性肺炎有关 在发展中国家，儿童是疾病和死亡的主要原因。5-15%的儿童骨量 骨髓移植患者会患上腺病毒感染；发病率从50%到80%不等。然而，几乎没有什么是 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。 识别这些宿主因素将有助于更好地设计抗病毒和免疫抑制疗法，并 以腺病毒为基础的基因治疗。小鼠腺病毒1型(MAV-1)提供了一种很好的动物模型 研究对传染病的易感性，因为它可以在自然宿主中研究，而且有 对MAV-1具有不同感受性的近交系。这项提案的目标是界定和 中国人巨噬细胞病毒1型易感主效QTL的宿主基因(S)特征分析 近亲繁殖的小鼠。中心假设是15号染色体上影响MAV-1易感性的主要QTL SJL/J小鼠含有一种免疫系统基因，在易感和耐药小鼠中是多态的。遗传 作图将与候选基因方法相结合，以达到两个特定的目标。(1)主效QTL 敏感度将使用几种互补的方法进行精细绘制。高密度的多态 标记将用于重组后代回交、杂交和第三代杂交的基因分型 小鼠(重组子代测试)。将构建一个区间特异性同源基因菌株，在该菌株中 来自敏感SJL/J小鼠的间隔将被导入到抗性BALB/CJ背景中。其他内容 将对近亲交配的小鼠品系进行测试，以确定它们是否与 SJL/J小鼠的主效QTL。如果是这样，它们将被用于精细定位、单倍型分析和候选基因 身份证明。(2)比较15号染色体QTL的20-30个候选基因 敏感品系和抗性品系的序列和基因表达差异。一个候选基因将会 通过将其替换为敏感等位基因而在抗性品系中进行基因鉴定和测试。该项目 预计将确定以前未描述的int？ractiorT^eerrK6sfiTrmrne res 免疫逃避，从而增加我们对病毒感染和宿主反应机制的了解 病原体。~