Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention

器官移植的蛋白质基因组学：预测、诊断、干预

• 批准号: 8131698
• 负责人: Michael M Abecassis
• 金额: $ 210.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131698
• 关键词: Acute; Address; Applications Grants; Atrophic; Benchmarking; Biological Assay; Biological Markers; Biopsy; Biotechnology; Blood; Calcineurin inhibitor; Cells; Chronic; Chronic Kidney Failure; Chronic Kidney Insufficiency; Chronic rejection of renal transplant; Clinical; Clinical Management; Clinical Services; Collaborations; Complex; Complication; Controlled Study; Creatinine; Custom; Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Dose; Drug toxicity; Equilibrium; Etiology; Event; Face; Fibrosis; Functional disorder; Gene Expression Profile; Genes; Heart; Heart Transplantation; Hypertension; Immune; Immunity; Immunosuppression; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Injury; Intervention; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Literature; Liver; Measures; Mediating; Medical; Medicine; Messenger RNA; Metabolic syndrome; Metric; Microarray Analysis; Molecular; Monitor; Nephrotoxic; Organ; Organ Transplantation; Outcome; Pain; Patients; Pharmaceutical Preparations; Plasma; Prediabetes syndrome; Process; Proteins; Proteomics; Protocols documentation; Renal function; Reperfusion Therapy; Research Personnel; Risk; Risk Factors; Safety; Serum; Services; Signal Transduction; Step Tests; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Transplant Recipients; Transplantation; Tubular formation; Validation; Work; base; design; effective intervention; genome-wide; injury prevention; interstitial; kidney allograft; liver transplantation; minimally invasive; nephrotoxicity; peripheral blood; prevent; programs; prospective; risk sharing; success

DESCRIPTION (provided by applicant): The unifying principle of this proposal is that post-transplant renal injury is a complex process that leads to progressive, chronic renal insufficiency and constitutes a major clinical barrier to the success of organ transplants. We believe there is now opportunity in transplant proteogenomics to investigate what is common and unique in the biomarker signatures and mechanisms of immunity, drug toxicity and the concomitant medical risk factors that drive renal injury in kidney, liver and heart transplant patients. Additionally, in heart and liver patients it is now clear that progressive kidney dysfunction is common and devastating. There is a pressing medical need for a minimally invasive, objective metric of optimal immunosuppression to monitor therapy and insure long-term success. However, another pressing need is also evident: a sensitive metric of early, non-immune renal injury that pre-dates creatinine elevations and allows individualized therapeutic interventions before irreversible renal damage is present. Specific Aim 1 is to validate proteogenomic-based, peripheral blood biomarker panels in a serial and prospective monitoring strategy in kidney transplant recipients including protocol kidney biopsies. We are testing the hypotheses that they will diagnose as well as predict acute rejection and the progressive sub-clinical renal injury that ultimately results in chronic allograft nephropathy with interstitial fibrosis and tubular atrophy. Specific Aim 2 is a prospective blood and biopsy monitoring study in liver and heart transplant recipients using the biomarker panels for acute rejection and chronic renal injury that were discovered and validated in kidney transplants. We are testing the hypothesis that the chronic kidney injury in renal allografts and the chronic native kidney disease of liver and heart transplant recipients involve a set of shared mechanisms. We also propose that there are shared mechanisms for acute rejection and tissue injury in all organ transplants that will be reflected in peripheral blood proteogenomic assays. The development and validation of minimally-invasive biomarkers to diagnose, let alone predict, acute rejection and chronic kidney tissue injury, would be a major advance in the clinical management of kidney, liver and heart transplant recipients and a big step toward the ability to individualize post-transplant therapy for optimal efficacy and safety. RELEVANCE: Immunosuppression prevents organ rejection; however, it increases other medical risks including renal injury in liver, kidney, and heart transplant patients. There is presently no adequate, minimally invasive measure to inform the optimal balance of immunosuppression efficacy and risk on an individual patient basis. This study will develop blood biomarker-based metrics as a benchmark for adequate, long-term immunosuppression and detect non-immune renal injury before creatinine elevations are present.

描述（由申请人提供）：该提案的统一原则是移植后肾损伤是一个复杂的过程，会导致进行性慢性肾功能不全，并构成器官移植成功的主要临床障碍。我们相信，现在移植蛋白基因组学有机会研究生物标志物特征和免疫机制、药物毒性以及导致肾、肝和心脏移植患者肾损伤的伴随医疗风险因素的常见和独特之处。此外，现在已经清楚，在心脏病和肝病患者中，进行性肾功能障碍是常见且具有破坏性的。医学界迫切需要一种微创、客观的最佳免疫抑制指标来监测治疗并确保长期成功。然而，另一个紧迫的需求也是显而易见的：早期非免疫性肾损伤的敏感指标，可以在肌酐升高之前进行，并允许在出现不可逆的肾损伤之前进行个体化的治疗干预。具体目标 1 是在肾移植受者（包括方案肾活检）的一系列前瞻性监测策略中验证基于蛋白质组学的外周血生物标志物组。我们正在测试这些假设，即它们将诊断并预测急性排斥反应和进行性亚临床肾损伤，最终导致伴有间质纤维化和肾小管萎缩的慢性同种异体移植肾病。具体目标 2 是一项针对肝脏和心脏移植受者的前瞻性血液和活检监测研究，使用在肾移植中发现和验证的急性排斥反应和慢性肾损伤生物标志物组。我们正在检验这样的假设：同种异体肾移植物中的慢性肾损伤以及肝脏和心脏移植受者的慢性天然肾病涉及一组共同的机制。我们还提出，所有器官移植中存在共同的急性排斥和组织损伤机制，这将反映在外周血蛋白质组学检测中。开发和验证微创生物标志物来诊断（更不用说预测）急性排斥反应和慢性肾组织损伤，将是肾、肝和心脏移植受者临床管理的重大进步，也是朝着实现个体化移植后治疗以获得最佳疗效和安全性的能力迈出的一大步。 相关性：免疫抑制可防止器官排斥；然而，它会增加其他医疗风险，包括肝脏、肾脏和心脏移植患者的肾损伤。目前还没有足够的微创措施来告知个体患者免疫抑制疗效和风险的最佳平衡。这项研究将开发基于血液生物标志物的指标，作为充分、长期免疫抑制的基准，并在肌酐升高出现之前检测非免疫性肾损伤。