Multi-omic Biomarker Discovery and Validation in Heart Transplant Patient Populations

项目总结/摘要 尽管在心脏移植患者管理方面取得了重大进展， 在过去的十年里，心脏同种异体移植物一直保持静止。提高和降低成本， 各种基因组学、转录组学、蛋白质组学、代谢组学和其他组学技术 过去十年，深度表型和电子健康记录的扩展提供了独特的 精准医疗的机会。 在这项提案中，我们概述了一些关键的多组分子研究和整合 分析以连接心脏移植患者的基因组和动态生理学。我们的目标 诊断和预测急性同种异体移植排斥反应，并评估生物标志物的影响 移植后并发症，包括急性排斥反应，从各种组学， 使用我们团队中的研究人员开发的“综合个人组学分析”（iPOP）。我们 概述了心脏移植急性排斥反应分子诊断的转变进展 在福尔马林固定石蜡包埋（FFPE）心脏移植物活检样本中， 改变目前仅使用传统组织病理学分级的护理标准。 我们还将评估遗传多态性如何影响其他组学概况，在同一个， 随后的时间点，从同一个人，直到移植后的复杂 表型如急性排斥反应。我们的目标是研究HLA中的遗传变异， 次要组织相容性（mHA）区域影响临床相关的移植后结局 包括急性排斥和患者存活率。

PROJECT SUMMARY/ABSTRACT Despite major advances in heart transplant patient management, 1 and 5-year survival rates for heart allografts have remained static over the last decade. Advances, and cost reduction, in various genomic, transcriptomic, proteomic, metabolomics and other omic technologies over the last decade, and the scaling of deep phenotyping and electronic health records affords unique opportunities for precision medicine. In this proposal we outline a number of key multiomic molecular studies and integrative analyses to bridge the genome and dynamic physiology in cardiac transplant patients. We aim to diagnose and prognosticate acute allograft rejection and to assess the impact of biomarkers of post-transplantation complications including acute rejection, from the various omics across using ‘integrative personal omic profiling’ (iPOP) developed by investigators in our team. We outline a transformation advance in the molecular diagnoses of acute cardiac allograft rejection within the formalin-fixed paraffin embedded (FFPE) heart allograft biopsy samples, which may change the current standard-of-care which uses conventional histopathology grading alone. We will also assess how genetic polymorphisms impact other omic profiles in the same-, and in subsequent-, timepoints from the same individuals through to post-transplantation complex phenotypes such as acute rejection. We aim to investigate how genetic variants in the HLA and minor histocompatibility (mHA) regions impact clinically relevant post-transplantation outcomes including acute rejection and patient survival.