GENETIC BASIS OF RECURRENT URINARY TRACT INFECTION

复发性尿路感染的遗传基础

• 批准号: 3078934
• 负责人: Ann E Stapleton
• 金额: $ 7.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3078934
• 关键词: Escherichia coli infections; family genetics; female; human subject; pathologic process; relapse /recurrence; urinary tract infection

Dr. Ann Stapleton is an Acting Instructor in Infectious Diseases who has completed four years of clinical and research fellowship training under the supervision of Dr. Walter E. Stamm. During her fellowship, Dr. Stapleton achieved board certification in infectious diseases and initiated research studies focusing on the pathogenesis of urinary tract infections (UTIs) in women. She has developed laboratory skills both in molecular biology and in biochemical methods of studying host glycolipid (GL) receptors on human epithelial cells. Dr. Stapleton excelled as a researcher during her fellowship period and is strongly committed to a career in basic research and academic medicine. The research and training program proposed here will allow Dr. Stapleton to develop the additional basic laboratory skills in glycolipid biochemistry that will enable her to become an independent investigator. She will be directly supervised by faculty who have extensive experience in glycolipid biochemistry (Dr. Hakomori and Nudelman) and the pathogenesis of urinary tract infections (Dr. Stamm). The extensive laboratory and clinical facilities and resources of both The Biomembrane Institute and the University of Washington will provide an excellent training environment for Dr. Stapleton. The candidate proposes to study the interactions between infecting E. coli, receptors on vaginal and uroepithelial cells and the patients' secretor status. An increased risk of recurrent UTI in women has been associated with both the nonsecretor state and with increased adherence of E. coli to uroepithelial cells from these patients. In preliminary work, she demonstrated that a radiolabelled wildtype E. coli isolate expressing the P and F adhesions specifically binds to two unique GLs in extracts of vaginal epithelial cells from nonsecretors but not secretors. These exciting results imply that nonsecretors have a genetic predisposition to recurrent UTI and suggest a specific biochemical basis for this predisposition. To confirm these findings, Dr. Stapleton has isolated and purified the GLs from urinary tract tissues. In addition, she will study vaginal epithelial cells from nonsecretors and secretors to determine the density, accessibility and binding affinity of relevant GL receptors for uropathogenic E. coli. Finally, she will also test the glycolipid binding characteristics of additional E. coli isolates with known P/F phenotypes. The results of these studies will provide important insights into the pathogenesis of UTI and may lead to the development of novel means for preventing recurrent infections.

安·斯台普顿博士是传染病的代理讲师，她有 完成了四年的临床和研究奖学金培训 沃尔特·E·斯塔姆博士的监督。在她担任研究员期间， 斯台普顿获得传染病和 以尿路发病机制为重点的初步研究 女性的尿路感染(UTIs)。她发展了实验室技能，包括 研究宿主糖脂的分子生物学和生化方法 人上皮细胞上的(GL)受体。斯台普顿博士是一位出色的 在她的研究员期间，她坚定地致力于 从事基础研究和学术医学。研究和培训 这里提出的计划将允许斯台普顿博士开发出额外的 糖脂生物化学方面的基本实验室技能将使她 成为一名独立调查员。她将受到直接监督 由在糖脂生物化学方面有丰富经验的教员(Dr。 与尿路感染的发病机制 (Stamm博士)广泛的实验室和临床设施以及 生物膜研究所和华盛顿大学的资源 华盛顿将为博尔顿博士提供良好的培训环境。 斯台普顿。 这位候选人建议研究感染E. 大肠杆菌，阴道和尿路上皮细胞上的受体以及患者的 保密者状态。女性尿路感染复发的风险增加 与非分泌者状态和增加的粘附性有关 从这些患者的尿路上皮细胞中分离出大肠杆菌。在预赛中 工作中，她证明了一种放射性标记的野生型大肠杆菌分离株 表达P和F粘连可与两个独特的GL特异结合 非分泌物而不是分泌物的阴道上皮细胞的提取物。 这些令人兴奋的结果表明，非分泌者有一种基因 有复发尿路感染的倾向，并建议有特定的生化基础 因为他的这种倾向。为了证实这些发现，斯台普顿博士 从尿路组织中分离纯化GLS。此外, 她将研究非分泌者和分泌者的阴道上皮细胞 以确定相关的密度、可访问性和结合亲和力 致尿路病原性大肠杆菌的GL受体。最后，她还将测试 新分离的大肠杆菌的糖脂结合特性 已知的P/F表型。这些研究的结果将提供重要的 对UTI发病机制的见解可能会导致UTI的发展 预防复发感染的新方法。