Babesiosis as a model of age-related immunosenescence

巴贝虫病作为年龄相关免疫衰老的模型

• 批准号: 7533186
• 负责人: Edouard G Vannier
• 金额: $ 34.67万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533186
• 关键词: Acute; Affect; Age; Age-Months; Alleles; Babesia microti; Babesiosis; Backcrossings; Bioinformatics; Borrelia microti; CD8B1 gene; Candidate Disease Gene; Cell physiology; Cells; Chromosomes; Chronic; Complex; Congenic Mice; Consomic Strain; DBA/2 Mouse; Data; Dendritic Cells; Elderly; Erythrocytes; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Goals; Human; Immune; Immune response; Inbred BALB C Mice; Individual; Infection; Maps; Modeling; Molecular Profiling; Monitor; Morbidity - disease rate; Mus; Numbers; Parasitemia; Phagocytosis; Phase; Phenotype; Population; Predisposition; Production; Public Health; Quantitative Trait Loci; Resistance; Spleen; T-Lymphocyte; Testing; Validation; Western World; Work; age related; aged; base; cohort; cytokine; defined contribution; experience; genetic analysis; immune resistance; immunosenescence; interest; macrophage; mouse model; positional cloning; research study; response; trait

DESCRIPTION (provided by applicant): As people age, a greater number becomes susceptible to infections. Because the aged represent an ever-growing segment of the populations in the western world, morbidities due to infection are significant. We are interested in identifying alleles that underlie this age-acquired susceptibility. We developed a mouse model of human babesiosis due Babesia microti, an emerging infection particularly severe in the aged. We observed that young DBA/2 mice experience significant parasitemia but young C57BL/6, B10.D2 and BALB/c mice do not. In DBA/2 mice an early phase characterized by an intense and transient parasitemia is followed by a late phase of low grade, but persistent parasitemia. As age advances, both acute and chronic parasitemia become greater in DBA/2, but not in C57BL/6, B10.D2 or BALB/c mice. Using B10.D2 x DBA/2 (BXD) and BALB/c x DBA/2 (CXD) crosses as well as chromosome substitution mice, we have established that i) resistance is a complex trait in young and old mice, and ii) acute resistance in young mice maps to QTL that differ from those of old mice. We conclude that the greater susceptibility of old DBA/2 mice maps to age-restricted QTL. We now propose to identify resistance and susceptibility alleles and to uncover how they modulate the response to B. microti infection. In Aim#1, we will identify the major genetic determinants of acute resistance in old mice of the BXD cross. In Aim#2, we will identify the major genetic determinants of acute resistance in old mice of the CXD cross. Both aims combine a positional cloning approach with bioinformatic analyses and gene expression studies. In Aim#3, we will identify the cells that contribute to resistance and are affected by the polymorphisms underlying the major QTL. Strain differences in cell function will be studied and used to guide the genetic analysis. We are hopeful that the identification of age-sensitive polymorphisms that modulate immune resistance of old mice to babesiosis may inform the search of alleles that predispose aged individuals to infection. PUBLIC HEALTH RELEVANCE: As they age, many people become more susceptible to infection. The reasons are poorly understood. We are exploring the genes that render aged mice susceptible to infection. Because there is great similarity between the genes of mice and humans we believe our discoveries in mice will aid work to understand the genetic basis of age-related susceptibility to infection in humans.

描述（由申请人提供）：随着人们的年龄，更多的人数容易受到感染的影响。由于老年人代表了西方世界中不断增长的人群，因此感染引起的病态意义很大。我们有兴趣识别这一年龄获得易感性的基础的等位基因。我们开发了一种小鼠贝贝斯病的小鼠模型，这是贝贝西亚微动物，这是一种新兴的感染。我们观察到年轻的DBA/2小鼠患有明显的寄生虫病，但年轻的C57BL/6，B10.D2和BALB/C小鼠没有。在DBA/2小鼠中，以强烈而短暂的寄生虫血症为特征的早期阶段之后是低级的后期，但持续的寄生虫病。随着年龄的增长，急性和慢性寄生虫血症在DBA/2中都变得更大，但在C57BL/6，B10.D2或BALB/C小鼠中均变得更大。使用B10.D2 X DBA/2（BXD）和BALB/C X DBA/2（CXD）杂交以及染色体取代小鼠，我们确定I）i）i）耐药性是年轻小鼠的复杂性状，ii）II）与QTL的急性抗性与QTL的急性抗性，与QTL相比，与老鼠不同。我们得出的结论是，旧的DBA/2小鼠对年龄限制的QTL的敏感性更大。现在，我们建议识别耐药性和敏感性等位基因，并发现它们如何调节对微芽孢杆菌感染的反应。在AIM＃1中，我们将确定BXD十字旧小鼠急性抗性的主要遗传决定因素。在AIM＃2中，我们将确定CXD交叉旧小鼠急性抗性的主要遗传决定因素。这两个目标都将位置克隆方法与生物信息学分析和基因表达研究结合在一起。在AIM＃3中，我们将确定有助于抗性的细胞，并受到主要QTL背后的多态性影响。细胞功能的应变差异将被研究并用于指导遗传分析。我们希望，对年龄敏感的多态性的鉴定可以调节旧小鼠对Babesiosis的免疫抵抗力，这可能会告知人们对倾向于年龄个体感染的等位基因的搜索。公共卫生相关性：随着年龄的增长，许多人变得更容易感染。原因知之甚少。我们正在探索使老年小鼠容易感染的基因。因为小鼠和人类的基因之间存在很大的相似性，所以我们认为我们在小鼠中的发现将有助于工作，以了解与年龄相关的人类感染的遗传基础。