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

项目摘要/摘要 尽管心脏移植患者管理取得了重大进展，但患者的1年和5年生存率 在过去的十年里，同种异体心脏移植一直保持不变。预付款和降低成本 各种基因组、转录组、蛋白质组、代谢组学和其他基因组学技术 在过去的十年里，深度表型和电子健康记录的规模提供了独特的 精准医疗的机遇。 在这项建议中，我们概述了一些关键的多组体分子研究和综合 连接心脏移植患者基因组和动态生理学的分析。我们的目标是 诊断和预测同种异体移植急性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，来自不同的组学 使用我们团队研究人员开发的“综合个人基因组图谱”(IPOP)。我们 同种异体心脏移植急性排斥反应分子诊断研究进展 在福尔马林固定石蜡包埋(FFPE)的同种异体心脏移植活检样本中，可以 改变目前仅使用常规组织病理学分级的护理标准。 我们还将评估基因多态如何影响同一和 从相同个体到移植后并发症的后续时间点 急性排斥反应等表型。我们的目标是研究人类白细胞抗原和人类白细胞抗原中的遗传变异 次要组织相容(MHA)区域影响临床相关移植后结果 包括急性排斥反应和患者存活率。

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.