ANDROGEN INFLUENCE ON UTI SUSCEPTIBILITY AND SEVERITY

项目摘要 在本项目中，我们将采用一种新的泌尿道感染（UTI）模型，在雌性和雄性小鼠中阐明 雄激素对这些感染的易感性和严重性的影响。以前的研究 性激素对UTI影响仅限于雌激素暴露。然而，我们最近的发现 表明性别，特别是雄激素暴露对这些常见细菌感染的影响， 比以前认识到的更复杂。到目前为止，UTI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管插入术。因此，膀胱感染（膀胱炎）和膀胱炎的临床前建模 肾脏感染（肾盂肾炎）以前几乎只在雌性小鼠中进行。在 为了应对这一赤字，我们最近开发，优化，并发表了一种新颖的，创新的，最低限度的 侵入性外科膀胱接种技术，允许首次研究UTI的性别差异 发病机制和宿主反应。我们的方法直接膀胱接种尿路致病性大肠杆菌 （UPEC）绕过了传统的性别解剖学差异， 雄性和雄激素化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 数据显示患有复杂性UTI的男性的发病率和死亡率较高（与女性相比）， 在患有常见高雄激素性疾病（多囊卵巢综合征）的女性中，UTI的发病率更高。 基于这些发现，我们推测雄激素增强上皮细胞对尿路致病性 细菌和/或影响宿主对女性和男性泌尿道细菌感染的免疫应答， 男性宿主为了质疑这一假设，我们建议首先证明观察到的表型来自于 通过雄激素受体信号传导;这将涉及用DHT（一种特异性AR）雄激素化的雌性小鼠 激动剂）以及药理学AR抑制剂。接下来，我们将定义和询问雄激素对两者的影响， 利用多种免疫学方法， 和新产生的C3 H/HeN条件性AR敲除小鼠。最后，我们将采取多个在 确定雄激素对泌尿上皮生物学的影响以及与 尿路致病菌我们的研究结果将阐明雄激素对女性和 男性宿主，发病机制和主机的反应，在下，上尿路感染。此外，我们的临床前 研究结果也将与多个人类患者人群中的UTI风险相关，包括 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.