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，并构成器官移植成功的主要临床障碍。我们相信，现在有机会在移植蛋白基因组学研究什么是共同的和独特的生物标志物的签名和免疫机制，药物毒性和伴随的医疗风险因素，驱动肾损伤的肾脏，肝脏和心脏移植患者。此外，在心脏和肝脏患者中，现在很明显，进行性肾功能障碍是常见的和毁灭性的。目前迫切需要一种微创、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是显而易见的：早期非免疫性肾损伤的敏感指标，早于肌酐升高，并允许在不可逆的肾损伤出现之前进行个性化的治疗干预。具体目标1是在肾移植受者（包括方案肾活检）的系列和前瞻性监测策略中验证基于蛋白基因组学的外周血生物标志物组。我们正在测试的假设，他们将诊断以及预测急性排斥反应和进行性亚临床肾损伤，最终导致慢性移植物肾病与间质纤维化和肾小管萎缩。Specific Aim 2是一项在肝脏和心脏移植受者中进行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的生物标志物组。我们正在验证这样一个假设，即肾移植中的慢性肾损伤和肝脏和心脏移植受者的慢性自体肾脏疾病涉及一套共同的机制。我们还建议，有共同的机制，急性排斥反应和组织损伤，在所有器官移植，将反映在外周血蛋白基因组学检测。开发和验证用于诊断（更不用说预测）急性排斥反应和慢性肾组织损伤的微创生物标志物将是肾、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反应;然而，它会增加其他医疗风险，包括肝、肾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功效和风险的最佳平衡。本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，并在肌酐升高之前检测非免疫性肾损伤。

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.