Viral and host predictors of BK polyomavirus associated hemorrhagic cystitis

项目摘要/摘要 这项建议的总体目标是研究膀胱损伤(出血性膀胱炎)的机制。 接受骨髓移植的儿童和年轻人与BK多瘤病毒(BKPyV)感染相关 移植(异基因造血细胞移植，HSCT)。BKPyV相关性出血性膀胱炎 高达25%的异基因造血干细胞移植受者的并发症。出血性膀胱炎导致患者发病 排尿疼痛，住院时间延长，输血要求增加，以及侵入性手术 当出现尿路梗阻时。出血性膀胱炎每发作一次就增加10家医院 几天，价格是7万美元。在其最严重的表现中，出血性膀胱炎可能与 有死亡的危险。在80%的HSCT受者中可以检测到尿液中的BKPyV复制，但不是所有这些人 患者会患上出血性膀胱炎。目前还没有被证实对BKPyV有效的抗病毒疗法 目前出血性膀胱炎的治疗策略仅限于支持性护理。一个主要障碍是 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 在BKPyV复制的患者中。这也阻止了对最高风险的患者的识别 膀胱受伤。这一建议的中心假设是，HSCT后出血性膀胱炎的风险是 BKPyV亚型和宿主对病毒的反应的功能。为了检验我们的假设，我们将研究两个 单独的前瞻性观察队列：由193名儿童和年轻人组成的现有小组，他们接受了 辛辛那提儿童医院医学中心或费城儿童医院的异基因HSCT 已经储存的尿样和一个由200名儿童和年轻人组成的独立验证队列 同种异体造血干细胞移植将在获奖期间在这两个中心进行登记。该项目的具体目标 以下是：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，并纳入验证队列；2)检测宿主细胞 出血性膀胱炎患者和非出血性膀胱炎患者的反应或特定基因多态性不同 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。此应用程序中的数据包括 对于确定出血性膀胱炎风险最高的患者将从细胞疗法中受益至关重要 以及其他有针对性的、未来的预防或治疗战略。

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.