Viral and host predictors of BK polyomavirus associated hemorrhagic cystitis

BK 多瘤病毒相关出血性膀胱炎的病毒和宿主预测因子

• 批准号: 10029242
• 负责人: JASON T BLACKARD
• 金额: $ 72万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029242
• 关键词: Age; Allogenic; Antiviral Agents; Antiviral Therapy; Award; BK Virus; Bladder; Bladder Injury; Blood Transfusion; Blood specimen; Bone Marrow Transplantation; Case-Control Studies; Cell Therapy; Chemotherapy-Oncologic Procedure; Child; Childhood; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Combination Drug Therapy; Complication; Cox Models; Cystitis; Data; Disease; Engraftment; Enrollment; Evaluation; Foundations; Future; Gender; Gene Deletion; Genes; Genetic Polymorphism; Genetic Variation; Genome; Glycoproteins; Goals; HIV/HCV; Hemorrhage; Hospital Costs; Hospitalization; Immune response; Incidence; Individual; Infection; Infusion procedures; Injury; Inpatients; Knowledge; Lead; Length; Length of Stay; Medical center; Membrane; Modeling; Molecular; Morbidity - disease rate; Mutation; Obstruction; Outcome; Pain; Participant; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Persons; Philadelphia; Polyomavirus Infections; Population; Prevention strategy; Procedures; Proteins; Proteomics; Questionnaires; RNA; ROC Curve; Research; Research Project Grants; Resolution; Risk; Sample Size; Sampling; Sensitivity and Specificity; Supportive care; T-Lymphocyte; Testing; Time; Transfusion; Transplant Recipients; Urination; Urine; Validation; Variant; Vesicle; Viral; Viral Physiology; Virulence; Virus; base; chemotherapy; cohort; conditioning; cost; exosome; graft vs host disease; hematopoietic cell transplantation; high risk; immune reconstitution; improved; mortality; mortality risk; neutrophil; next generation sequencing; novel; novel therapeutics; patient oriented; predictive modeling; prevent; prospective; response; targeted treatment; transcriptome sequencing; transcriptomics; treatment strategy; urinary; urinary tract obstruction; virus genetics; young adult

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.

项目摘要/摘要 该提案的总体目标是研究膀胱损伤的机制（出血性膀胱炎） 与患有骨髓的儿童和年轻人的BK多瘤病毒（BKPYV）感染有关 移植（同种异体造血细胞移植，HSCT）。 BKPYV相关的出血性膀胱炎是 多达25％的同种异体HSCT接受者的并发症。出血性膀胱炎导致患者发病 排尿疼痛，住院时间长，输血要求增加和侵入性程序 当存在尿反对时。出血性膀胱炎的每一集占10个医院 天数和$ 70,000。在最严重的表现中，出血性膀胱炎可能与较高的 死亡风险。可以在80％的HSCT接受者中检测到尿液中的BKPYV复制，但并非全部 患者将患上出血性膀胱炎。没有针对BKPYV的抗病毒疗法 出血性膀胱炎的当前治疗策略仅限于支持护理。一个主要障碍 开发和测试新型疗法是我们缺乏了解膀胱损伤机制 在BKPYV复制的患者中。这也防止了对患者的识别 膀胱受伤。该提议的中心假设是，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：现有的193名儿童和年轻人的组 辛辛那提儿童医院医疗中心或费城儿童医院的同种异体HSCT与 已经存放了尿液样本和200名儿童和年轻人的独立验证队列 同种异体HSCT将在奖励期间在这两个中心注册。该项目的具体目的 为：1）测试患者和 HSCT后没有出血性膀胱炎并招募验证队列； 2）测试是否宿主蜂窝 反应或特定基因多态性在患有和没有出血性膀胱炎的受试者之间是不同的 HSCT使用蛋白质组学和转录组学方法后。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。该应用程序的数据是 对于确定将受益于细胞疗法的出血性膀胱炎风险最高的患者至关重要 以及其他有针对性的未来预防或治疗策略。