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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

由于尿路感染的主要并发症是频繁复发，因此似乎存在致命的缺陷在泌尿免疫系统中。膀胱的一个明显特征，似乎有助于他们对再感染的易感性是发生高度非典型组织重塑每次感染后，膀胱都容易受到未来的感染。因为很少有目前已知关于膀胱重塑，对此主题的研究可能会揭示新的策略对抗复发性尿路感染。我们假设由于高度细胞毒性和尿液的高渗性，膀胱开始剧烈的上皮化和重塑每次感染后快速恢复丢失的上皮的计划。我们的初步研究验证了这一观点，并揭示了被招募到膀胱中的 T 细胞更专门于指导组织修复（Th2）而不是消除病原体（Th1）。因此，感染者感染解决后，膀胱中的细菌并未完全消除，使这个器官在未来容易爆发。由于组织修复 T 细胞被招募到膀胱往往会持续存在，并且可能会因再次感染而迅速引起，其程度重塑程序高，显着影响膀胱排尿能力。我们发现与膀胱修复计划相关的关键免疫调节剂是一个不同的子类树突状细胞 (DC)，在膀胱癌后不久就会移动到膀胱上皮下区域表面上皮细胞丧失。在此，我们建议确定这个DC的具体角色上皮修复的子类。我们还将检查 T 的 Th2 偏见的根本基础感染后细胞重新进入膀胱。最后，我们将调查将 Th2 引发的膀胱反应重新编程为 Th1 型反应的可能性使用与 Th1 共同施用的疫苗抗原对幼稚小鼠和慢性感染小鼠进行免疫偏向佐剂。我们怀疑此类疫苗不仅能保护膀胱免受未来的影响感染，但也使这些小鼠的膀胱功能恢复