Utility of Biomarkers of Rejection and Kidney Injury in Tailoring Liver Transplant Immunosuppression
排斥和肾损伤生物标志物在调整肝移植免疫抑制中的效用
基本信息
- 批准号:10651862
- 负责人:
- 金额:$ 182.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-06 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAntibodiesBenefits and RisksBiological MarkersBloodCalcineurin inhibitorCellsCellular AssayChronic Kidney FailureClinicalClinical DataClinical TrialsCommunitiesComplicationDataDecision MakingDeteriorationDiagnosticDialysis procedureDiseaseDrug toxicityEarly DiagnosisEquilibriumExcisionFRAP1 geneFibrosisFutureGene ExpressionGenerationsGenomicsGlomerular Filtration RateGraft SurvivalHypoxiaImmuneImmune responseImmunosuppressionInjury to KidneyInterventionKidneyKidney TransplantationLiverMagnetic Resonance ImagingModelingMonitorMulti-Institutional Clinical TrialMulticenter TrialsOutcomePathway interactionsPatient SelectionPatientsPharmaceutical PreparationsPhenotypePhysiologicalPlasma ProteinsPropertyProteomicsRandomizedRegimenRegulatory T-LymphocyteRenal functionResearchResourcesRiskRoleSDZ RADSamplingScienceSurfaceT-LymphocyteTacrolimusTestingTherapeuticTherapeutic immunosuppressionTimeTransplant RecipientsTransplantationTransplanted Liver ComplicationWeaningWithdrawalWorkbiobankbiomarker performancebiomarker signaturebiomarker validationclinical practicecohorteffector T cellexhaustionfrontierhigh riskimaging biomarkerimmune activationimprovedinhibitorinhibitor therapyinsightkidney imagingkidney preservationliver transplantationloss of functionmTOR Inhibitormolecular diagnosticsmolecular markernephrotoxicitynew therapeutic targetnovelpatient stratificationpre-clinicalpredictive markerpreservationpreventprimary endpointprimary outcomeprospectiveproteogenomicsrenal ischemiaresponserisk stratificationsample collectionstandard of caretechnology platformtreatment strategyvalidation studies
项目摘要
Project Summary/Abstract
The advent of molecular biomarkers holds great promise, both from a diagnostic perspective as well as the ability
to predict a disease state early enough to inform therapy and change clinical outcomes. In the last several years,
studies have suggested a role for biomarker profiling in the management of immunosuppression in liver
transplant recipients. From our CTOT-14 study data, we have developed key biomarkers that can detect early
signs of under- (rejection) and over- (chronic kidney disease) immunosuppression, particularly with use of
standard calcineurin-inhibitor therapy. But as the accuracy of molecular diagnostics improves, and as technology
platforms evolve, two important questions have surfaced regarding their value in the management of liver
transplant recipients. First, can biomarkers inform patient management and optimize the ability to personalize
immunosuppressive therapy? Second, can we characterize key pathways of immune activation and kidney injury
to further optimize the use of biomarkers and identify new therapeutic targets? We believe that these questions
comprise the next frontier in biomarker research, and we have therefore formulated this proposal to test a set of
hypotheses that relate directly to these questions. First, in a prospective multi-center clinical trial of liver
transplant recipients, we will challenge the `standard of care' and test the hypothesis that serial blood biomarker
profiling can identify patients at risk of kidney injury after liver transplantation and also guide the removal of
nephrotoxic calcineurin-inhibitor therapy safely without adversely increasing acute rejection. To achieve this
objective, we will leverage these immune and kidney biomarkers developed in our CTOT-14 validation study to
detect early signs of rejection and kidney injury to enhance proactive, safe withdrawal of calcineurin-inhibitors in
favor of non-nephrotoxic mTOR-inhibitors. This biomarker-guided interventional approach will be tested against
current standard management and also risk-stratify patients into those needing or not needing such
interventions. Second, we will leverage the clinical trial sample collections to gain deeper understanding of what
leads to rejection or alternatively what is protective of rejection. We will accomplish this by performing an
extensive battery of blood immune cell, antibody, genomic and proteomic profiling during the interventions to
best identify the pathways leading to our outcomes. In addition, we will simultaneously perform novel kidney
imaging biomarkers to ask what leads to kidney injury vs. protection in our unique cohorts. Together, the clinical
trial and accompanying mechanistic studies will allow us to cross the next frontier in biomarker research in
transplantation, namely the ability to use biomarkers to monitor the state of immune responsiveness and drug
toxicity to inform therapeutic decisions. Our clinical data and bio-banked samples will create a new resource for
the community and facilitate a new generation of molecular diagnostics translatable into clinical practice.
项目总结/文摘
项目成果
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JOSH LEVITSKY的其他文献
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{{ truncateString('JOSH LEVITSKY', 18)}}的其他基金
Utility of Biomarkers of Rejection and Kidney Injury in Tailoring Liver Transplant Immunosuppression
排斥和肾损伤生物标志物在调整肝移植免疫抑制中的效用
- 批准号:
10482420 - 财政年份:2021
- 资助金额:
$ 182.71万 - 项目类别:
Utility of Biomarkers of Rejection and Kidney Injury in Tailoring Liver Transplant Immunosuppression
排斥和肾损伤生物标志物在调整肝移植免疫抑制中的效用
- 批准号:
10282762 - 财政年份:2021
- 资助金额:
$ 182.71万 - 项目类别:
Proteomic Predictors of Chronic Kidney Disease in Liver Transplant Recipients
肝移植受者慢性肾病的蛋白质组预测因子
- 批准号:
8759709 - 财政年份:2014
- 资助金额:
$ 182.71万 - 项目类别:
Proteomic Predictors of Chronic Kidney Disease in Liver Transplant Recipients
肝移植受者慢性肾病的蛋白质组预测因子
- 批准号:
8898662 - 财政年份:2014
- 资助金额:
$ 182.71万 - 项目类别:
PROBIOTICS: A NEW APPROACH TO CORRECT INTESTINAL PERMEABILITY
益生菌:纠正肠道渗透性的新方法
- 批准号:
7604320 - 财政年份:2006
- 资助金额:
$ 182.71万 - 项目类别:
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