Cloning a major gene for mouse adenovirus susceptibility

克隆小鼠腺病毒易感性主要基因

基本信息

批准号：
7846601
负责人：
Katherine R. Spindler
金额：
$ 7.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846601
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

项目摘要

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. ~

腺病毒会导致 5-10% 的儿童呼吸道疾病，并与儿童急性肺炎有关发展中国家的儿童，这是导致 5-15% 儿童骨骼疾病和死亡的主要原因。骨髓移植患者发生腺病毒感染；发病率在 50-80% 之间，但这种情况很少。了解腺病毒发病机制，特别是宿主因素对疾病易感性的贡献。识别此类宿主因素将有助于更好地设计抗病毒和免疫抑制疗法，基于腺病毒的基因治疗1型小鼠腺病毒（MAV-1）提供了一个极好的模型。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，并且有对 MAV-1 具有不同敏感性的近交株本提案的目的是定义和表征 MAV-1 易感性主要数量性状位点 (QTL) 的宿主基因中心假设是 15 号染色体上的 MAV-1 易感性的主要 QTL。 SJL/J 小鼠含有易感和耐药小鼠的多态性免疫系统基因。作图将与候选基因方法相结合，以实现两个具体目标（1）主要 QTL。敏感性将使用几种互补的方法进行精细绘制。标记将用于重组后代回交、间交和第三代杂交的基因分型小鼠（重组后代测试）将构建区间特异性同源品系，其中易感 SJL/J 小鼠的间隔将渗入到抗性 BALB/cJ 背景中。将测试近交系小鼠品系，以确定它们是否与其他小鼠品系具有相同的易感性遗传基础。 SJL/J 小鼠中的主要 QTL 如果是这样，它们将用于精细作图、单倍型分析和候选基因。 (2) 将比较 15 号染色体 QTL 的 20-30 个候选基因的列表。敏感菌株和抗性菌株之间的序列和基因表达差异。通过用易感等位基因替换抗性菌株来对其进行鉴定和基因测试。预计会识别出先前未描述的 int¿ actiorT^ieT^eerrK6sfiTrTrmrne 资源免疫逃避，从而增加我们对病毒感染和宿主反应机制的了解病原体。