Aberrant remodeling of bladder following infection

感染后膀胱异常重塑

基本信息

批准号：
10381529
负责人：
Soman N Abraham
金额：
$ 40.17万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381529
关键词：
Acute Adjuvant Age Allergens Asthma Bacteria Biological Response Modifiers Bladder Bladder mucosa Cells Chronic Complication Defect Dendritic Cells Development Devices Disease Epithelial Exposure to Flare Frequencies Future Goals Health Immune Immune response Immune system Immunity Immunization Immunize Incidence Increased frequency of micturition Infection Infective cystitis Inflammatory Interleukin-12 Interleukin-4 Lamina Propria Link Mediating Mus Nature Organ Patients Population Predisposition Preventative vaccination Process Production Recording of previous events Recovery Recurrence Resolution Risk Factors Role T-Lymphocyte Th1 Cells Tissues Urinary tract infection Urine Vaccine Antigen Vaccines cell type combat cytotoxic epithelial repair epithelium regeneration experience pathogen programs recruit recurrent infection repaired response tissue repair urinary vaccination strategy

项目摘要

Since a major complication of UTIs is frequent recurrence, there appears to be a fateful defect in the urinary immune system. A distinct feature of the bladder which appears to contribute to their susceptibility to reinfection is the high degree of atypical tissue remodeling that occurs following each infection, predisposing the bladder to future infections. Since very little is currently known regarding bladder remodeling, studies on this topic may reveal new strategies to combat recurrent UTIs. We have hypothesized that because of the highly cytotoxic and hyperosmolar nature of urine, the bladder initiates a vigorous re-epithelization and remodeling program to rapidly recover lost epithelium after each infection. Our preliminary studies have validated this notion and revealed that T cells recruited into the bladder are more specialized in directing tissue repair (Th2) than in pathogen elimination (Th1). Consequently, the infecting bacteria in the bladder are not completely eliminated following resolution of infection, predisposing this organ to future flare-ups. Since the tissue repair T cells recruited into the bladder tend to persist and could be quickly evoked with reinfection, the magnitude of the remodeling program is high, significantly impacting bladder voiding capacity. We have found that a critical immune regulator associated with the bladder repair program is a distinct subclass of dendritic cells (DCs), which moves into the subepithelial region of the bladder soon after the loss of the superficial epithelium. Here, we propose to determine the specific role of this DC subclass in epithelial repair. We will also examine the underlying basis for the Th2 bias of T cells recruited into the bladder following bouts of infection. Finally, we will investigate the possibility of reprograming Th2 primed bladder response into a Th1 type response by immunizing naïve and chronically infected mice with a vaccine antigen co-administered with Th1 biasing adjuvant. We suspect that such vaccines will not only protect bladder from future infection but also permit recovery of bladder function in these mice

由于UTI的主要并发症经常复发，因此似乎存在命运的缺陷在尿液免疫系统中。膀胱的独特特征似乎有助于它们对重新感染的敏感性是发生的高度非典型组织重塑在每种感染之后，将膀胱倾向于将来的感染。因为很少目前知道有关膀胱重塑的知识，有关此主题的研究可能会揭示新的策略打击反复发作的尿路感。我们假设由于高度细胞毒性和尿液的高颜色性质，膀胱启动剧烈的重新上述和重塑每次感染后迅速恢复失去上皮的程序。我们的初步研究验证了这个概念，并揭示了募集到膀胱中的T细胞更专业指导组织修复（TH2）比消除病原体（TH1）。因此，感染膀胱中的细菌没有完全消除感染后，将这种器官诱发到未来的爆发中。由于组织修复T细胞募集到膀胱嫩的持久，可以通过再感染迅速唤起，重塑程序很高，严重影响了膀胱排序能力。我们找到了与膀胱维修计划相关的关键免疫调节器是一个独特的子类树突状细胞（DCS），该细胞在膀胱后不久进入膀胱的下皮下区域浅表上皮的丧失。在这里，我们建议确定该DC的具体作用上皮修复中的子类。我们还将检查t的Th2偏差的基本基础关于感染后，细胞招募到膀胱中。最后，我们将调查通过将Th2重编程的可能性通过用与TH1共同采用的疫苗抗原免疫幼稚和长期感染的小鼠偏置佐剂。我们怀疑这种疫苗不仅会保护膀胱免受未来感染但也允许在这些小鼠中恢复膀胱功能