Proteogenomics for Organ Transplantation: Prediction, Diagnosis, Intervention

描述（由申请人提供）：本提案的统一原则是，移植后肾损伤是一个复杂的过程，可导致进行性慢性肾功能不全，是器官移植成功的主要临床障碍。我们相信移植蛋白质基因组学现在有机会研究导致肾、肝和心脏移植患者肾损伤的生物标志物特征和免疫机制、药物毒性以及伴随的医疗风险因素中的共同和独特之处。此外，在心脏和肝脏患者中，现在很清楚进行性肾功能障碍是常见的和毁灭性的。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，另一个迫切的需求也很明显：早期非免疫性肾损伤的敏感指标，在肌酐升高之前，允许在不可逆肾损害出现之前进行个体化治疗干预。具体目标1是验证基于蛋白质基因组学的外周血生物标志物面板在肾移植受者的一系列和前瞻性监测策略中，包括协议肾活检。我们正在测试这样的假设，即它们将诊断和预测急性排斥反应和最终导致慢性同种异体移植肾病伴间质纤维化和肾小管萎缩的进行性亚临床肾损伤。Specific Aim 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，使用在肾脏移植中发现并验证的急性排斥反应和慢性肾损伤的生物标志物面板。我们正在验证一种假设，即同种异体肾移植的慢性肾损伤和肝脏和心脏移植受者的慢性先天性肾病涉及一系列共同的机制。我们还提出，在所有器官移植中，急性排斥反应和组织损伤都有共同的机制，这将反映在外周血蛋白基因组学分析中。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，也是向个性化移植后治疗能力迈出的一大步，以获得最佳疗效和安全性。

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.