Genomics of Susceptibility to Urinary Tract Infections

描述（由申请方提供）：成年女性的复发性尿路感染（鲁蒂）是患者发病率的重要来源，在某些情况下可导致长期肾损伤。正在进行的研究旨在确定导致易感性增加的宿主因素;然而，迄今为止，还没有明确不同固有宿主因素的相对重要性。更好地了解内在宿主因素的遗传基础，将有可能设计出克服遗传缺陷的新疗法，并开发出早期发现易感个体的筛查方法。 RUTI很可能有很强的家族易感性，并且在小鼠中已经证明了遗传决定的对严重膀胱和肾脏感染的易感性。增加细菌感染性或损害有效免疫反应的特定基因尚未在小鼠或人类中确定。先天性和适应性免疫反应在解决UTI和预防上尿路感染方面发挥着重要作用;然而，这些反应的确切性质，它们的相互依赖性及其遗传基础尚未完全了解。因此，拟议的研究的总体目标是使用基因组方法和手段来阐明UTI易感性的遗传学，并描绘内在的宿主因子和免疫功能，这些因子和免疫功能对于宿主对UTI的抗性是重要的。本研究的具体目的是：1）验证小鼠中特定的遗传位点与对诱导的E.利用DNA微卫星染色体标记对泌尿道感染耐药小鼠和敏感小鼠进行遗传连锁分析，筛选出与这些耐药基因同源的小鼠品系; coil赋予对由其他E.大肠杆菌菌株或非大肠杆菌细菌。这些目标将使用完善的上行性UTI小鼠模型、遗传连锁分析和同类小鼠对尿路病原体的抗性评价来实现。

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.