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: 10653831
• 负责人: JASON T BLACKARD
• 金额: $ 67.47万
• 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/10653831
• 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; 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; Specificity; Supportive care; T-Lymphocyte; Testing; Time; Transfusion; Transplant Recipients; Urination; Urine; Validation; Variant; Vesicle; Viral; Viral Physiology; Virulence; Virus; 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（异基因造血细胞移植，HSCT）。 BKPyV 相关的出血性膀胱炎是 高达 25% 的同种异体 HSCT 受者会出现这种并发症。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手术 当存在尿路梗阻时。出血性膀胱炎每次发作需额外住院10次 天并花费 70,000 美元。在最严重的表现中，出血性膀胱炎可能与较高的发病率有关。 死亡风险。 80% 的 HSCT 受者尿液中可检测到 BKPyV 复制，但并非所有受者 患者会出现出血性膀胱炎。目前尚无已证实对 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治疗。的一个主要障碍 开发和测试新疗法是我们缺乏对膀胱损伤机制的了解 存在 BKPyV 复制的患者。这也妨碍了识别出感染风险最高的患者 膀胱损伤。该提案的中心假设是 HSCT 后发生出血性膀胱炎的风险是 BKPyV 亚型的功能和宿主对病毒的反应。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 奖励期内将在这两个中心进行同种异体造血干细胞移植。该项目的具体目标 是： 1) 测试群体或人体内的 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纳入验证队列； 2) 测试宿主细胞是否 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 使用蛋白质组学和转录组学方法进行 HSCT 后。这项研究的结果预计将提高我们的 了解造血干细胞移植后膀胱损伤的病毒和宿主机制。该应用程序的数据是 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。

项目成果

BK Polyomavirus Subtypes II and IV in Hematopoietic Cell Transplant Recipients.

• DOI: 10.1128/mra.01053-21
• 发表时间: 2022-01-20
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Odegard EA;Meeds HL;Kleiboeker SB;Ziady A;Sabulski A;Jodele S;Seif AE;Davies SM;Laskin BL;Blackard JT
• 通讯作者: Blackard JT

BK Polyomavirus Genotypes in Two Patients after Hematopoietic Cell Transplant.

• DOI: 10.1128/mra.01122-20
• 发表时间: 2021-01-14
• 期刊: Microbiology resource announcements
• 影响因子: 0.8
• 作者: Odegard EA;Meeds HL;Kleiboeker SB;Ziady A;Sabulski A;Jodele S;Davies SM;Laskin BL;Blackard JT
• 通讯作者: Blackard JT

Optimized amplification of BK polyomavirus in urine.

• DOI: 10.1016/j.jviromet.2021.114319
• 发表时间: 2022-01
• 期刊: Journal of virological methods
• 影响因子: 3.1
• 作者: Odegard EA;Meeds HL;Kleiboeker SB;Ziady A;Sabulski A;Jodele S;Seif AE;Davies SM;Laskin BL;Blackard JT
• 通讯作者: Blackard JT

BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

造血干细胞移植后的 BK 多瘤病毒多样性。

• DOI: 10.1093/infdis/jiad117
• 发表时间: 2023
• 期刊: The Journal of infectious diseases
• 作者: Odegard,ElizabethA;Meeds,HeidiL;Kleiboeker,StevenB;Ziady,Assem;Sabulski,Anthony;Jodele,Sonata;Seif,AlixE;Davies,StellaM;Laskin,BenjaminL;Blackard,JasonT
• 通讯作者: Blackard,JasonT