Metagenomic shotgun microbial sequencing in post-transplant lymphoproliferative disorders (PTLD-MSMS)
移植后淋巴增殖性疾病的宏基因组鸟枪法微生物测序 (PTLD-MSMS)
基本信息
- 批准号:10426126
- 负责人:
- 金额:$ 56.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-10 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlgorithmic SoftwareAmino AcidsArchivesBelgiumBiological AssayBiological MarkersCell TransplantationCessation of lifeCharacteristicsClinicalClinical DataClinical PathologyCodeCollectionCommunicable DiseasesComplicationComputational algorithmDNADNA VirusesDataDatabasesDiagnosisEpidemiologyEtiologyEventFormalinFrightGenesGenomicsGoalsGroupingHematopathologyHumanHuman GenomeHuman Herpesvirus 4Immune systemImmunosuppressionInternationalKnowledgeLiteratureLocationLymphoid CellLymphoproliferative DisordersMalignant - descriptorMetagenomicsMorbidity - disease rateNucleic AcidsOncogenesOncogenicOncogenic VirusesOncologyOrgan TransplantationOutcomeParaffin EmbeddingPathogenicityPathologicPatient CarePatientsPennsylvaniaPlasmaPrognosisPublishingRNARegistriesResearchResourcesRoleSample SizeSamplingSeveritiesShotgun SequencingShotgunsSiteSolidSpecialistSuggestionTechniquesTechnologyTimeTissue ExtractsTissue SampleTissuesTransplant RecipientsTransplantationUniversitiesVariantViralViral GenomeVirusWashingtonabstractinganalytical toolbasecohortdata managementgenetic variantgenome sequencinggenomic datahigh riskhuman DNAmetagenomic sequencingmicrobialmicrobial genomicsmortalitymultidisciplinarymutantnovelnovel therapeuticspost-transplantprecision medicinepredictive modelingprognostic indexprogramsprospectivereference genomerepositorysample fixationstatisticstissue archivetooltranscriptome sequencingtranslational genomicstumorviral DNAviral detectionwhole genome
项目摘要
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) remain a feared malignant complication of
transplantation, with high 5-year mortality and morbidity exceeding 50%. About 50-80% of cases are strongly
related to the oncogenic Epstein-Barr virus (EBV), a key pathogenic driver. Many knowledge gaps exist in
PTLD. Several prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics,
including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting an
additional role for EBV genome variants or other viral etiologies. However, the precision medicine tools for
determining if a viral genome variant is pathogenic are very limited compared to human genome variants.
Further, the etiological agent in EBV-negative PTLD is unknown. Using novel recently developed cutting-edge
technologies, we can extract viral nucleic acids from formalin-fixed, paraffin-embedded archived PTLD tissues
or plasma and sequence multiple viruses simultaneously in unbiased fashion, using metagenomic shotgun
sequencing (MSS) and ViroCap™. Based on our preliminary data, we propose a precision medicine
translational genomics project to address the following specific aims and close the cited knowledge gaps: 1)
Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by other
techniques) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; 2)
Determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral
groupings, confirmed by other techniques; 3) Develop the necessary computational, algorithmic and software
analytic tools required to then determine association of EBV genome variants with worse presentations or
outcomes in PTLD. To achieve these aims, we will retrospectively collect PTLD tissues and prospectively
collect PTLD tissues/plasma from: 1) cases at Washington University that have occurred after 2015; 2) three
USA sites with large transplant programs and existing PTLD collections (Universities of Pennsylvania,
Pittsburgh and Stanford; 3) a French national-level PTLD registry that already has extensive clinical data and
can obtain archived tissues. In this proposed sample size of adequately powered 630 PTLD cases, we will: a)
acquire tissue scrolls from the PTLD samples and transport to Washington University; b) extract the microbial
DNA and RNA; c) perform metagenomic shotgun sequencing; and d) validate our novel associations to the
clinical data, imported from each of the sites, into an already constructed RedCap database. Our team includes
specialists in transplantation, hematopathology, infectious diseases, oncology, genomics, data management
and statistics. Our preliminary data, collaborators and local resources are exceptional to accomplish these
goals. This study will additionally create the largest-to-date repository of combined PTLD tissue, extracted
nucleic acids, and well-annotated clinical and pathological data, for use in further research. Completion of this
study will contribute to better patient care and may provide avenues for novel therapies.
摘要
移植后淋巴组织增生性疾病(PTLD)仍然是移植后的一种令人担忧的恶性并发症。
移植,5年死亡率高,发病率超过50%。大约50-80%的病例是强烈的
与致癌性EB病毒(EBV)相关,这是一种关键的致病驱动因素。许多知识差距存在于
PTLD。几个预后指标,包括多个临床,流行病学和肿瘤特征,
包括EBV肿瘤阳性,并不总是与患者生存率较差相关,这表明
EBV基因组变异或其他病毒病因的额外作用。然而,精准医疗工具,
与人类基因组变体相比,确定病毒基因组变体是否是致病性的非常有限。
此外,EBV阴性PTLD的病因尚不清楚。使用新的最新开发的尖端技术
技术,我们可以从福尔马林固定,石蜡包埋存档的PTLD组织中提取病毒核酸
或血浆,并使用宏基因组鸟枪法以无偏的方式同时对多种病毒进行测序
测序(MSS)和ViroCap™。根据我们的初步数据,我们提出了一种精确医学,
翻译基因组学项目,以解决以下具体目标,并缩小所引用的知识差距:1)
证实了我们的新观察,即通过MSS检测的PTLD组织对环节病毒呈阳性(并通过其他方法证实)。
技术)作为PTLD诊断后移植受体死亡率较高的生物标志物; 2)
通过多种病毒的无偏MSS确定其他致癌病毒在EBV阴性PTLD中的作用
分组,通过其他技术确认; 3)开发必要的计算,算法和软件
需要分析工具来确定EBV基因组变异与更差表现的关联,
PTLD的结果。为了实现这些目标,我们将回顾性收集PTLD组织,
收集PTLD组织/血浆:1)华盛顿大学2015年后发生的病例; 2)3例
具有大型移植项目和现有PTLD收集的美国研究中心(宾夕法尼亚大学,
匹兹堡和斯坦福大学; 3)法国国家级PTLD登记研究,已经有广泛的临床数据,
可以获得存档的组织。在充分把握度的630例PTLD病例的拟定样本量中,我们将:a)
从PTLD样品中获取组织卷并运输到华盛顿大学; B)提取微生物
DNA和RNA; c)进行宏基因组鸟枪测序; d)验证我们与DNA和RNA的新关联。
从每个站点导入的临床数据,导入到已经构建的RedCap数据库中。我们的团队包括
移植、血液病理学、传染病、肿瘤学、基因组学、数据管理方面的专家
和统计数据。我们的初步数据,合作者和当地资源是完成这些任务的特殊条件。
目标.这项研究还将创建迄今为止最大的PTLD组织库,
核酸,以及注释良好的临床和病理学数据,用于进一步的研究。完成本
这项研究将有助于更好的病人护理,并可能为新的治疗方法提供途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Vikas R. Dharnidharka其他文献
Biomarkers to detect rejection after kidney transplantation
- DOI:
10.1007/s00467-017-3712-6 - 发表时间:
2017-06-19 - 期刊:
- 影响因子:2.600
- 作者:
Vikas R. Dharnidharka;Andrew Malone - 通讯作者:
Andrew Malone
Utilization of anti-CD20 antibodies for treatment of childhood nephrotic syndrome, 2010 to 2022
- DOI:
10.1007/s00467-025-06811-4 - 发表时间:
2025-06-05 - 期刊:
- 影响因子:2.600
- 作者:
Michelle R. Denburg;Kathryn Hirabayashi;Amy Goodwin Davies;Hanieh Razzaghi;Vikas R. Dharnidharka;Bradley P. Dixon;Joseph T. Flynn;Caroline A. Gluck;Mark M. Mitsnefes;William E. Smoyer;Susan L. Furth;Christopher B. Forrest - 通讯作者:
Christopher B. Forrest
The BK virus in renal transplant recipients—review of pathogenesis, diagnosis, and treatment
- DOI:
10.1007/s00467-010-1716-6 - 发表时间:
2011-10-01 - 期刊:
- 影响因子:2.600
- 作者:
Vikas R. Dharnidharka;Husam A. Abdulnour;Carlos E. Araya - 通讯作者:
Carlos E. Araya
Gadolinium and nephrogenic fibrosing dermopathy in pediatric patients
- DOI:
10.1007/s00467-006-0384-z - 发表时间:
2007-09-01 - 期刊:
- 影响因子:2.600
- 作者:
Vikas R. Dharnidharka;Stanton K. Wesson;Robert S. Fennell - 通讯作者:
Robert S. Fennell
Pediatric Nephrology Practice in the United States: Survey of Pediatric Nephrology Division Directors
美国儿科肾脏病学实践:儿科肾脏病学部门主任调查
- DOI:
10.1053/j.ajkd.2025.01.025 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:8.200
- 作者:
Priya S. Verghese;Amy Bobrowski;Caitlin Carter;Vikas R. Dharnidharka;Jyothsna Gattineni;Julie E. Goodwin;David B. Kershaw;Teri J. Mauch;Raoul Nelson;Mihail Subtirelu;Joseph Flynn;Daniel Feig;Carolyn L. Abitbol;Sandra Amaral;Diego Aviles;Richard T. Blaszak;Lavjay Butani;Caitlin E. Carter;Prasad Devarajan;Bradley P. Dixon;Christine Sethna - 通讯作者:
Christine Sethna
Vikas R. Dharnidharka的其他文献
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{{ truncateString('Vikas R. Dharnidharka', 18)}}的其他基金
Understanding the immune response changes to clinical interventions for Epstein-Barr virus infection prior to lymphoma development in children after organ transplants (UNEARTH)
了解器官移植后儿童淋巴瘤发展之前针对 Epstein-Barr 病毒感染的临床干预的免疫反应变化(UNEARTH)
- 批准号:
10755205 - 财政年份:2023
- 资助金额:
$ 56.77万 - 项目类别:
Metagenomic shotgun microbial sequencing in post-transplant lymphoproliferative disorders (PTLD-MSMS)
移植后淋巴增殖性疾病的宏基因组鸟枪法微生物测序 (PTLD-MSMS)
- 批准号:
10630142 - 财政年份:2019
- 资助金额:
$ 56.77万 - 项目类别:
Metagenomic shotgun microbial sequencing in post-transplant lymphoproliferative disorders (PTLD-MSMS)
移植后淋巴增殖性疾病的宏基因组鸟枪法微生物测序 (PTLD-MSMS)
- 批准号:
9816875 - 财政年份:2019
- 资助金额:
$ 56.77万 - 项目类别:
Metagenomic shotgun microbial sequencing in post-transplant lymphoproliferative disorders (PTLD-MSMS)
移植后淋巴增殖性疾病的宏基因组鸟枪法微生物测序 (PTLD-MSMS)
- 批准号:
10180895 - 财政年份:2019
- 资助金额:
$ 56.77万 - 项目类别:
Choosing Immune Suppression in Renal Transplantation by Efficacy and Morbidity
根据疗效和发病率选择肾移植中的免疫抑制
- 批准号:
8913168 - 财政年份:2014
- 资助金额:
$ 56.77万 - 项目类别:
Choosing Immune Suppression in Renal Transplantation by Efficacy and Morbidity
根据疗效和发病率选择肾移植中的免疫抑制
- 批准号:
9529611 - 财政年份:2014
- 资助金额:
$ 56.77万 - 项目类别:
Choosing Immune Suppression in Renal Transplantation by Efficacy and Morbidity
根据疗效和发病率选择肾移植中的免疫抑制
- 批准号:
9135342 - 财政年份:2014
- 资助金额:
$ 56.77万 - 项目类别:
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