Genomics of Susceptibility to Urinary Tract Infections

描述(由申请人提供)：成年女性反复的尿路感染(RUTI)是患者发病率的重要来源，在某些情况下可能导致长期的肾脏损害。正在进行的研究旨在确定有助于增加易感性的宿主因素；然而，对于不同固有宿主因素的相对重要性，目前还没有一个明确的图景。更好地了解固有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，并开发筛查方法，以早期发现易感个体。 RUTIs很可能有很强的家族易感性，并且已经在小鼠身上证明了遗传决定的对严重的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老鼠或人类身上确定。先天性和获得性免疫反应在解决尿路感染和预防上呼吸道感染方面发挥着重要作用；然而，这些反应的确切性质、它们的相互依存关系和它们的遗传基础尚不完全清楚。因此，本研究的总体目标是利用基因组学途径和方法来阐明尿路感染易感性的遗传学，并描述在宿主对尿路感染的抗性中起重要作用的内在宿主因子和免疫功能。这项建议的具体目的是：1)通过使用DNA微卫星染色体标记对UTI耐药和易感小鼠进行遗传连锁分析，验证特定基因座与小鼠对诱导性膀胱炎和肾脏感染的易感性或抵抗力增加相关的假设，并选择性地培育与这些耐药基因同源的小鼠品系；2)测试与一株致尿路致病性埃希氏菌诱导的膀胱和肾脏感染的抗性相关的基因使其对其他大肠杆菌株或非E型线圈细菌引起的类似感染具有抵抗力的假设。这些目标将通过建立尿路感染上升的小鼠模型、遗传连锁分析和评估同种基因小鼠对尿路病原体的抵抗力来实现。

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.