Viral and host predictors of BK polyomavirus associated hemorrhagic cystitis

项目概要/摘要 本提案的总体目标是研究膀胱损伤（出血性膀胱炎）的机制 与接受骨髓移植的儿童和年轻人中BK多瘤病毒（BKPyV）感染相关 异基因造血细胞移植（allogeneic hematopoietic cell transplantation，HSCT）BKPyV相关出血性膀胱炎是 高达25%的异基因HSCT接受者会出现并发症。出血性膀胱炎导致患者发病， 排尿疼痛、住院时间延长、输血需求增加和侵入性操作 当出现尿路梗阻时。出血性膀胱炎每发作一次， 时间和费用7万元。在其最严重的表现，出血性膀胱炎可能与较高的 死亡的风险。在80%的HSCT受者中可以检测到尿液中的BKPyV复制，但不是所有这些受者都是如此。 患者会发生出血性膀胱炎。目前尚无已证实对BKPyV有效的抗病毒疗法 并且目前对出血性膀胱炎的治疗策略限于支持性护理。的主要障碍 开发和测试新的治疗方法是我们缺乏对膀胱损伤机制的了解， BKPyV复制的患者。这也防止了识别出处于最高风险的患者， 膀胱损伤这项建议的中心假设是HSCT后出血性膀胱炎的风险是一个风险。 BKPyV亚型的功能和宿主对病毒的应答。为了验证我们的假设，我们将研究两个 单独的前瞻性观察队列：现有的193名儿童和年轻人， 在辛辛那提儿童医院医学中心或费城儿童医院进行同种异体HSCT， 已经储存的尿液样本和一个由200名儿童和年轻人组成的独立验证队列， 在这两个相同的研究中心，在奖励期间入组同种异体HSCT。项目的具体目标 是：1）测试人群或人内BKPyV多样性是否在患有和 HSCT后无出血性膀胱炎，并招募验证队列;和2）测试宿主细胞是否 有和无出血性膀胱炎的受试者之间的反应或特定基因多态性不同 在HSCT后使用蛋白质组学和转录组学方法。这项研究的结果预计将增加我们的 了解HSCT后膀胱损伤的病毒和宿主机制。此应用程序的数据为 这对于识别出血性膀胱炎风险最高的患者并从细胞治疗中获益至关重要 以及其他有针对性的未来预防或治疗策略。

PROJECT SUMMARY/ABSTRACT The overall goals of this proposal are to investigate the mechanisms of bladder injury (hemorrhagic cystitis) associated with BK polyomavirus (BKPyV) infection in children and young adults undergoing bone marrow transplantation (allogeneic hematopoietic cell transplantation, HSCT). BKPyV-associated hemorrhagic cystitis is a complication for up to 25% of allogeneic HSCT recipients. Hemorrhagic cystitis leads to patient morbidity from painful urination, prolonged hospitalizations, increased blood transfusion requirements, and invasive procedures when urinary obstruction is present. Each episode of hemorrhagic cystitis accounts for 10 additional hospital days and costs $70,000. In its most severe presentation, hemorrhagic cystitis may be associated with a higher risk of death. BKPyV replication in the urine can be detected in 80% of HSCT recipients, but not all of these patients will develop hemorrhagic cystitis. There are no antiviral therapies with proven efficacy against BKPyV and current treatment strategies for hemorrhagic cystitis are limited to supportive care. A major barrier to developing and testing novel therapies is our lack of understanding the mechanisms of bladder injury in patients with BKPyV replication. This also prevents the identification of the patients at highest risk for bladder injury. The central hypothesis of this proposal is that the risk of hemorrhagic cystitis after HSCT is a function of both BKPyV subtype and the host response to the virus. To test our hypothesis, we will study two separate prospective observational cohorts: an existing group of 193 children and young adults who received an allogeneic HSCT at Cincinnati Children’s Hospital Medical Center or the Children’s Hospital of Philadelphia with already banked urine samples and an independent validation cohort of 200 children and young adults undergoing allogeneic HSCT to be enrolled during the award period at these same two centers. The project’s specific aims are: 1) to test whether the population or within-person BKPyV diversity is different between patients with and without hemorrhagic cystitis after HSCT and to enroll the validation cohort; and 2) to test whether host cellular responses or specific gene polymorphisms are different between subjects with and without hemorrhagic cystitis after HSCT using proteomics and transcriptomics approaches. This study’s results are expected to increase our understanding of the viral and host mechanisms of bladder injury after HSCT. The data from this application are critical for identifying the patients at highest risk of hemorrhagic cystitis who would benefit from cellular therapies and other targeted, future prevention or treatment strategies.