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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该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 BK 多瘤病毒 (BKPyV) 感染相关移植（同种异体造血细胞移植，HSCT）是BKPyV相关的出血性膀胱炎。高达 25% 的同种异体 HSCT 受者会出现出血性膀胱炎的并发症，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手术当出现尿路梗阻时，出血性膀胱炎每次发作需额外住院 10 次。天和费用 70,000 美元在最严重的情况下，出血性膀胱炎可能与更高的死亡率有关。 80% 的 HSCT 接受者尿液中可检测到 BKPyV 复制，但并非所有接受者都有死亡风险。患者会出现出血性膀胱炎。目前尚无针对 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，这是治疗的主要障碍。开发和测试新疗法是我们缺乏对膀胱损伤机制的了解这也阻碍了对 BKPyV 复制风险最高的患者的识别。该提案的中心假设是 HSCT 后发生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 名儿童和年轻人接受了在辛辛那提儿童医院医疗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正在接受奖励期间将在这两个中心招募同种异体造血干细胞移植该项目的具体目标。是： 1) 测试群体或人体内 BKPyV 多样性在患有和的患者之间是否不同 HSCT 后无出血性膀胱炎并招募验证队列；2) 测试宿主细胞是否存在；患有和不患有出血性膀胱炎的受试者之间的反应或特定基因多态性是不同的在使用蛋白质组学和转录组学方法进行 HSCT 后，这项研究的结果有望提高我们的水平。了解 HSCT 后膀胱损伤的病毒和宿主机制。来自该应用的数据是。对于识别出血性膀胱炎风险最高的患者至关重要，这些患者将从细胞疗法中受益以及其他有针对性的未来预防或治疗策略。