ANDROGEN INFLUENCE ON UTI SUSCEPTIBILITY AND SEVERITY

项目总结 在这个项目中，我们将使用一种新的雌性和雄性小鼠的尿路感染模型来阐明 雄激素对这些感染的易感性和严重性的影响。以前的研究是关于 性激素对尿路感染的影响仅限于雌激素暴露。然而，我们最近的发现 表明性行为，尤其是雄激素暴露，对这些常见细菌感染的影响是 比之前想象的要复杂得多。到目前为止，尿路感染发病机制和宿主反应的性别差异 尚未在临床前模型中进行检查，主要是因为技术(解剖学)考虑排除了 雄性小鼠膀胱的常规导尿术。因此，临床前模拟膀胱炎(膀胱炎)和 肾脏感染(肾盂肾炎)以前几乎只发生在雌性小鼠身上。在……里面 针对这一不足，我们最近开发、优化并出版了一种新颖、创新、最低限度的 首次研究尿路感染性别差异的侵入性外科膀胱接种技术 致病机理和寄主反应。泌尿系致病性大肠杆菌膀胱直接接种方法的研究 绕过传统性别解剖差异的(UPEC)已经惊人地揭示了 雄性和雄激素雌性小鼠对慢性膀胱炎、严重肾盂肾炎、 上行性肾脓肿形成和肾小管间质纤维化。这些发现与流行病学相关。 数据显示，确实患有复杂性尿路感染的男性的发病率和死亡率更高(与女性相比)， 患有常见高雄激素性疾病(多囊卵巢综合征)的女性的尿路感染发生率较高。 在这些发现的基础上，我们假设雄激素增强了上皮细胞对泌尿系病原体的接受性。 细菌和/或影响宿主对细菌感染尿路的免疫反应 男性主持人。为了验证这一假设，我们建议首先证明观察到的表型起源于 通过雄激素受体发出信号；这将涉及用DHT(一种特定的AR)产生雄激素的雌性小鼠 激动剂)以及药理上的AR抑制剂。接下来，我们将定义和询问雄激素对这两种疾病的影响 宿主对膀胱和肾脏感染免疫反应的可溶性和细胞成分，使用多种 技术和新产生的C3H/HEN条件性AR基因敲除小鼠。最后，我们将接受多个 体外和体内研究雄激素对尿路上皮生物学的影响及其相互作用 泌尿系致病菌。我们的结果将阐明雄激素对女性和 男性宿主对上、下尿路感染发病机制和宿主反应的影响。此外，我们的临床前研究 研究结果还将与多个人类患者群体的尿路感染风险相关，包括 其他都是健康的女性。

PROJECT SUMMARY In this project, we will employ a new model of urinary tract infection (UTI) in female and male mice to illuminate the influence exerted by androgens on susceptibility to, and severity of, these infections. Prior studies of the influence of sex hormones on UTI have been limited to estrogen exposure only. However, our recent findings indicate that the influence of sex, particularly androgen exposure, on these common bacterial infections is more complex than previously appreciated. Until now, sex differences in UTI pathogenesis and host response have not been examined in preclinical models, largely because technical (anatomic) considerations preclude routine catheterization of the male mouse bladder. Thus, preclinical modeling of bladder infection (cystitis) and kidney infection (pyelonephritis) has previously been performed almost exclusively in female mice. In response to this deficit, we recently developed, optimized, and published a novel, innovative, minimally invasive surgical bladder inoculation technique that allows first-ever studies of sex differences in UTI pathogenesis and host response. Our method of direct bladder inoculation with uropathogenic Escherichia coli (UPEC), which bypasses traditional anatomic differences between sexes, has already revealed strikingly higher susceptibility of male and androgenized female mice to chronic cystitis, severe pyelonephritis, ascending renal abscess formation, and tubulointerstitial fibrosis. These findings correlate with epidemiologic data revealing higher morbidity and mortality in men who do suffer complicated UTI (compared with women), and higher incidence of UTI in women with a common hyperandrogenic condition (polycystic ovary syndrome). On the basis of these findings, we hypothesize that androgens enhance epithelial receptivity to uropathogenic bacteria and/or influence the host immune response to bacterial infection of the urinary tract in both female and male hosts. To interrogate this hypothesis, we propose to first prove that the observed phenotypes arise from signaling through the androgen receptor; this will involve female mice androgenized with DHT (a specific AR agonist) as well as pharmacologic AR inhibitors. Next, we will define and interrogate androgen effects on both the soluble and cellular components of host immune responses to bladder and kidney infection, using a variety of techniques and newly generated C3H/HeN conditional AR knockout mice. Finally, we will take multiple in vitro and in vivo approaches to defining androgen effects on uroepithelial biology and interactions with uropathogenic bacteria. Our results will illuminate the influence exerted by androgens, in both female and male hosts, on pathogenesis and host response in both lower and upper-tract UTI. In addition, our preclinical findings will also be translationally relevant to UTI risk in multiple human patient populations, including otherwise healthy women.