Host-Pathogen Interactions From Measurements of Urinary Cell Free DNA in Kidney Transplantation
肾移植中尿细胞游离 DNA 测量的宿主-病原体相互作用
基本信息
- 批准号:9375180
- 负责人:
- 金额:$ 24.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-26 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AllograftingAntibiotic TherapyBacteriaBacterial GenomeBiological AssayCellsClinicalComplicationDNA LibraryDataData SetDevelopmentEnd stage renal failureEvaluationGene ExpressionGenesGenetic FingerprintingsGenomicsGoalsGoldGrowthImmune responseImmunocompromised HostImmunologicsIncidenceInfectionInjuryKidney TransplantationLongevityMeasurementMessenger RNAMetagenomicsMonitorMorbidity - disease rateMulti-Drug ResistanceNatural ImmunityNucleosomesPathogenesisPatientsPilot ProjectsPopulationPreparationRecruitment ActivityRecurrenceRegulator GenesReplication OriginResolutionSamplingSequence AnalysisShotgun SequencingShotgunsSingle-Stranded DNASpecimenStructureStudy SectionSymbiosisTechniquesTestingTimeTissuesTranscription Initiation SiteTransplant RecipientsTransplantationUrinalysisUrinary tract infectionUrineVisitWorkadaptive immunitybasebiobankcell free DNAcell injuryco-infectioncohortdiagnosis standarddifferential expressionmicrobiomemicrobiotamortalitynovelpathogenpromoterresistance mutationresponsetoolurinary
项目摘要
Kidney transplantation is the preferred treatment option for end stage kidney disease, but infectious and
immunological complications limit the lifespan of kidney transplants. Urinary tract infections (UTI) occur at an
alarmingly high rate after kidney transplantation and are associated with urosepsis, allograft loss, and mortality.
The current gold standard for diagnosis of UTI is bacterial culture. Culture-based tests are, however, limited by
their ability to detect only culturable bacteria, do not inform about co-infections and commensal microbiota, do
not inform about bacterial growth dynamics, and do not inform about the host's response to infection.
The goal of this proposal is to invent and apply genomic assays of urinary cell-free DNA that can
simultaneously inform about the composition of the urinary microbiome, growth dynamics of pathogens
associated with UTI, tissue injury in the graft, and the host's immune response to infection. A unique
opportunity for this work is our large cohort of over 250 kidney transplant recipients in which we have serial
biobanked urine specimens as well as routine conventional urine cultures in the first 3 months of transplantation.
Using a newly developed single-stranded DNA library preparation technique, we will profile 290 urinary samples
for cfDNA: i) serial samples from transplant recipients with UTI (prior to, during, and after UTI) ii) serial samples
from recipients with recurrent UTIs; iii) samples from recipients with asymptomatic UTI and negative urinanalysis;
and iv) samples from recipients who do not develop UTI in the first 3 months of transplantation.
We will profile the dynamic urinary microbiome prior to, during, and after UTI in kidney transplantation.
We will investigate whether cfDNA profiles are associated with UTI as well as whether they can anticipate UTI,
UTI recurrence, and multi-drug resistant UTI. Based on the concept that bacterial genome replication rates and
growth dynamics can be estimated from analyses of metagenomic sequence coverage, we will estimate growth
dynamics over time and in response to antibiotic therapy in patients with UTI and recurrent UTI.
We will monitor the host response to UTI via analyses of nucleosome footprints comprised within cfDNA
and via donor specific cfDNA. Our pilot studies indicate that i) the structures of nucleosomal arrays in
transcriptional regulatory elements are preserved and comprised within urinary cfDNA, and ii) that an analysis
of nucleosomal occupancy in gene promoters can be used to quantify gene expression. We will investigate the
differential host's response in subjects who have symptomatic UTI with positive urinalysis and asymptomatic UTI
with negative urinalysis and the differential host's response in UTI patients after antibiotic treatment. We will
assess tissue injury to the allograft in the scope of UTI, using donor specific cfDNA as a marker of allograft injury.
Successful implementation of this proposal will provide a novel understanding of the pathogenesis of UTI as well
as open new avenues for the utilization of cfDNA profiling as a sensitive and noninvasive transplant monitoring
tool.
肾移植是终末期肾脏疾病的首选治疗方案,但感染性和
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(1)
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Iwijn De Vlaminck其他文献
Iwijn De Vlaminck的其他文献
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{{ truncateString('Iwijn De Vlaminck', 18)}}的其他基金
Cell-free DNA as a versatile analyte for the monitoring of sepsis
游离 DNA 作为监测脓毒症的多功能分析物
- 批准号:
10665402 - 财政年份:2023
- 资助金额:
$ 24.87万 - 项目类别:
A spatially resolved molecular atlas of acute viral myocarditis at single-cell resolution
单细胞分辨率的急性病毒性心肌炎的空间解析分子图谱
- 批准号:
10681925 - 财政年份:2023
- 资助金额:
$ 24.87万 - 项目类别:
Cell-Free DNA in Peritoneal Fluid as a Novel and Versatile Analyte for Monitoring Peritonitis
腹膜液中的游离 DNA 作为监测腹膜炎的新型多功能分析物
- 批准号:
10428638 - 财政年份:2021
- 资助金额:
$ 24.87万 - 项目类别:
Cell-Free DNA in Peritoneal Fluid as a Novel and Versatile Analyte for Monitoring Peritonitis
腹膜液中的游离 DNA 作为监测腹膜炎的新型多功能分析物
- 批准号:
10288893 - 财政年份:2021
- 资助金额:
$ 24.87万 - 项目类别:
Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation
循环游离 DNA 表观遗传分析用于监测造血细胞移植后移植物抗宿主病
- 批准号:
10328516 - 财政年份:2020
- 资助金额:
$ 24.87万 - 项目类别:
Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation
循环游离 DNA 表观遗传分析用于监测造血细胞移植后移植物抗宿主病
- 批准号:
10533829 - 财政年份:2020
- 资助金额:
$ 24.87万 - 项目类别:
Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation
循环游离 DNA 表观遗传分析用于监测造血细胞移植后移植物抗宿主病
- 批准号:
10084808 - 财政年份:2020
- 资助金额:
$ 24.87万 - 项目类别:
Droplet-Assisted RNA targeting by single-cell sequencing to dissect the single-cell heterogeneity of RNA virus infection
通过单细胞测序进行液滴辅助 RNA 靶向分析 RNA 病毒感染的单细胞异质性
- 批准号:
9888327 - 财政年份:2019
- 资助金额:
$ 24.87万 - 项目类别:
Precision monitoring of kidney transplants via single-cell and single-molecule sequencing
通过单细胞和单分子测序精确监测肾移植
- 批准号:
9350514 - 财政年份:2017
- 资助金额:
$ 24.87万 - 项目类别:
Mitochondrial Cell-Free DNA as a Marker of Rejection and Damage-Associated Molecular Pattern in Organ Transplantation
线粒体游离 DNA 作为器官移植中排斥和损伤相关分子模式的标记
- 批准号:
9335715 - 财政年份:2016
- 资助金额:
$ 24.87万 - 项目类别:
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