Genomics of Susceptibility to Urinary Tract Infections

尿路感染易感性基因组学

• 批准号: 6684947
• 负责人: WALTER J HOPKINS
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684947
• 关键词: Escherichia coli; Escherichia coli infections; disease /disorder model; family genetics; functional /structural genomics; genetic susceptibility; host organism interaction; immunity; immunogenetics; inbreeding; kidney infection; laboratory mouse; linkage mapping; urinary bladder disorder; urinary tract infection

DESCRIPTION (provided by applicant): Recurrent urinary tract infections (RUTI) in adult women are a significant source of patient morbidity and can lead to long-term kidney damage in some cases. Ongoing research is directed towards identifying host factors that contribute to increased susceptibility; however, as yet there is not a clear picture of the relative importance of different inherent host factors. A better understanding of the genetic basis of intrinsic host factors it will make it possible to devise new therapies that overcome genetic deficiencies and to develop screening methods for early detection of susceptible individuals. There is very likely a strong familial predisposition to RUTIs, and a genetically determined susceptibility to severe bladder and kidney infections has been demonstrated in mice. Specific genes that increase bacterial infectivity or impair effective immune responses have not yet been identified in mice or humans. Innate and adaptive immune responses play major roles in resolving UTIs and preventing upper tract infections; however, the exact nature of these responses, their interdependence, and their genetic basis is not fully understood. Therefore, the overall goal of the proposed research is to use genomic approaches and methods to elucidate the genetics of UTI susceptibility and to delineate intrinsic host factors and immune functions that are important for host resistance to UTIs. The specific aims of this proposal are: 1) to test the hypothesis that specific genetic loci in mice are associated with increased susceptibility or resistance to induced E. coil bladder and kidney infections by genetic linkage analysis of UTI-resistant and susceptible mice using DNA microsatellite chromosomal markers and selectively breed strains of mice that are congenic for these resistance genes and 2) to test the hypothesis that genes associated with resistance to bladder and kidney infections induced by one strain of uropathogenic E. coil confer resistance to similar infections caused by other E. coli strains or non-E, coil bacteria. These objectives will be accomplished using a well-established mouse model of ascending UTI, genetic linkage analysis, and evaluation of resistance to uropathogens in congenic mice.

描述（由申请人提供）：成年女性的尿路感染（RUTI）是患者发病率的重要来源，在某些情况下会导致长期肾脏损害。正在进行的研究旨在识别有助于提高易感性的宿主因素。但是，到目前为止，尚不清楚不同固有宿主因素的相对重要性。更好地理解内在宿主因素的遗传基础，它将有可能设计新的疗法来克服遗传缺陷，并开发筛查方法，以尽早发现易感人群。 在小鼠中，已经证明了对严重膀胱和肾脏感染的遗传确定的对严重膀胱和肾脏感染的易感性很可能具有强烈的家族性易感性。在小鼠或人类中尚未发现增加细菌感染或损害有效免疫检查的特定基因。先天和适应性免疫反应在解决UTI和防止上部感染方面起着重要作用；但是，这些反应的确切性质，它们的相互依赖性和它们的遗传基础尚未完全理解。因此，拟议的研究的总体目标是使用基因组方法和方法来阐明UTI易感性的遗传学，并描绘出对宿主对UTIS耐药性至关重要的内在宿主因素和免疫功能。该提案的具体目的是：1）检验以下假说：小鼠中的特定遗传基因座与对诱导的E. coil膀胱和肾脏感染的敏感性或抵抗力有关，通过对UTI的遗传连接分析和易感小鼠的遗传连接分析，使用DNA微卫星标志物以及对这些依赖于这些依赖的依赖的依赖的依赖依赖的依赖的依赖的依赖于这些依赖的依赖于这些依赖的依赖的依赖于这些依托的依赖于这些依赖的依托的依赖于这些依赖的依赖的依赖于这些依托的依赖于这些基因的基因依赖于这些基因的基因依赖性。具有抗膀胱和肾脏感染的耐药性，由一种尿液发育性E.线圈会赋予对其他大肠杆菌菌株或非E，NON-E，COIL细菌引起的相似感染的抗性。这些目标将使用良好的升级UTI的小鼠模型，遗传链接分析以及对尿道病的耐药性评估。