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ANDROGEN INFLUENCE ON UTI SUSCEPTIBILITY AND SEVERITY

雄激素对尿路感染易感性和严重程度的影响

基本信息

批准号：
9445746
负责人：
DAVID ALAN HUNSTAD
金额：
$ 34.99万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9445746
关键词：
Agonist Anatomy Androgen Receptor Androgenization Androgens Animal Model Anti-Bacterial Agents Bacteria Bacterial Infections Biology Bladder Bypass C3H/HeN Mouse Catheterization Cell Culture Techniques Cell Death Chronic Cystitis Communities Complement Complex Cystitis Data Epidemiology Epithelial Epithelial Cells Estradiol Estrogens Female Fibrosis Flow Cytometry Fluorescence Microscopy Genetic Gonadal Steroid Hormones Hematopoietic Histologic Histology Human Immune response In Vitro Incidence Infection Infective cystitis Injury Kidney Knockout Mice Male Castration Methods Modeling Morbidity - disease rate Mus Operative Surgical Procedures Outcome Ovariectomy Pathogenesis Patients Peripheral Pharmacology Phenotype Polycystic Ovary Syndrome Pre-Clinical Model Predisposition Publishing Pyelonephritis Receptor Signaling Risk Role Severities Sex Characteristics Signal Transduction Specific qualifier value Specificity Stanolone Stromal Cells Techniques Testosterone Transforming Growth Factor beta Tubular formation Urethra Urinary tract Urinary tract infection Uropathogenic E. coli Woman activin A cell type epidemiologic data functional outcomes in vivo inhibitor/antagonist innovation kidney infection macrophage male men minimally invasive mortality neutrophil novel patient population pre-clinical prevent recruit renal abscess response sex

项目摘要

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.

项目概要在这个项目中，我们将在雌性和雄性小鼠中采用一种新的尿路感染（UTI）模型来阐明雄激素对这些感染的易感性和严重程度的影响。之前的研究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别，尤其是雄激素暴露，对这些常见细菌感染的影响比以前想象的更复杂。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）考虑因素排除了雄性小鼠膀胱的常规导尿术。因此，膀胱感染（膀胱炎）的临床前建模和肾脏感染（肾盂肾炎）以前几乎只在雌性小鼠中进行。在为了应对这一缺陷，我们最近开发、优化并发布了一种新颖的、创新的、最低限度的侵入性手术膀胱接种技术首次研究尿路感染的性别差异发病机制和宿主反应。我们的尿路致病性大肠杆菌直接膀胱接种方法（UPEC）绕过了性别之间传统的解剖学差异，已经令人震惊地揭示了雄性和雄激素化雌性小鼠对慢性膀胱炎、严重肾盂肾炎的易感性较高上行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，患有复杂性尿路感染的男性发病率和死亡率较高（与女性相比），患有常见的雄激素过多症（多囊卵巢综合征）的女性尿路感染的发病率较高。根据这些发现，我们假设雄激素增强上皮对尿路致病性的接受性细菌和/或影响宿主对女性和泌尿道细菌感染的免疫反应男主持人。为了质疑这个假设，我们建议首先证明观察到的表型来自通过雄激素受体发出信号；这将涉及用 DHT（一种特定的 AR 激动剂）以及药理学 AR 抑制剂。接下来，我们将定义并询问雄激素对两者的影响使用多种方法研究宿主对膀胱和肾脏感染的免疫反应的可溶性和细胞成分技术和新生成的 C3H/HeN 条件 AR 敲除小鼠。最后，我们将采取多个定义雄激素对尿上皮生物学及其相互作用的体外和体内方法泌尿道致病细菌。我们的结果将阐明雄激素对女性和男性所产生的影响男性宿主，关于下尿路和上尿路感染的发病机制和宿主反应。此外，我们的临床前研究结果也将与多个人类患者群体的尿路感染风险相关，包括其他方面健康的女性。