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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之一是频繁和复发，因此似乎不会成为一种致命的尿路缺陷。在我们的尿液免疫系统中，膀胱有一个明显的特征，它似乎对癌症有很大的贡献。他们对再感染的易感性是这种情况下发生的非典型组织重塑的最高程度。在每次感染之后，都会使膀胱癌发生未来的感染。自那以来，几乎没有什么新的发现。目前已知的关于膀胱重塑的研究，可能会揭示新的重塑策略。为了抗击反复出现的尿路感染，我们已经假设了这一点，因为这种疾病具有高度的细胞毒性。高渗透压是尿液的本性，而膀胱则启动了一种非常活跃的上皮化过程和重塑。我们计划在每一次感染后迅速恢复丢失的上皮细胞。我们的初步研究已经完成。对这一概念的验证表明，被招募到膀胱癌中的T细胞在临床上具有更多的专门化功能。指导组织修复(Th2)比消除病原体(Th1)更重要。因此，更容易感染人。在感染得到解决后，膀胱液中的细菌还没有完全消除。这个器官的易感性可能会导致未来的突发事件。自从组织修复T细胞被招募到这个组织以来，T细胞就被招募到了医院。膀胱癌往往不会持续存在，而且它可能很快就会因再次感染而被唤起，这是癌症的主要严重性。重塑计划的成本非常高，显著影响了膀胱的排尿能力。我们已经发现。这是一个与膀胱癌修复计划相关的关键免疫器官监管机构，是一个截然不同的子类。术后不久，树突状细胞(DC)进入膀胱的上皮下区域。表面上皮细胞的丢失。在这里，我们可以提出一种方法来确定它在这个过程中的具体作用。上皮细胞修复中的子类问题。我们还将研究以下问题的潜在基础：T细胞的TTh2偏向。在一轮又一轮的感染之后，细胞被招募到膀胱中。最后，我们将继续调查这一事件。将Th2重新编程的可能性已准备好将膀胱癌的反应转变为Th1类型的反应。为幼稚的小鼠和慢性感染的小鼠接种新疫苗和抗原，并与TTh1共同接种。我们怀疑，这样的疫苗不仅不会保护膀胱癌免受未来的伤害。感染不仅可以使这些小鼠的膀胱功能恢复正常，而且还可以使小鼠的膀胱功能恢复正常。