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

心脏移植患者群体中多组学生物标志物的发现和验证

基本信息

批准号：
10373122
负责人：
MARIO C. DENG
金额：
$ 78.65万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10373122
关键词：
Acute Allogenic Allografting Autoantibodies Biological Biological Markers Biology Biopsy Biopsy Specimen Blood Cardiac Chronic Classification Clinical Clinical Trials Complex DNA DNA analysis Data Data Set Development Diagnosis Diagnostic Disease Electronic Health Record Evaluation Event Failure Formalin Freezing Genetic Genetic Polymorphism Genome Genomics Genotype Gold Heart Heart Transplantation Histocompatibility Histologic Histology Histopathology Immune Immune response Individual Interobserver Variability Knowledge Maps Minor Minor Histocompatibility Antigens Molecular Molecular Diagnosis Nature Organ Outcome Paraffin Embedding Patients Peptides Phenotype Physiology Plasma Procedures Process Prognosis Prognostic Marker Proteomics RNA Reading Research Personnel Risk Sampling Sensitivity and Specificity Site Solid Standardization Survival Rate Symptoms Technology Testing Therapeutic immunosuppression Time Tissue Embedding Tissues Transplant Recipients Transplantation Validation Variant Vascular Diseases allograft rejection antibody-mediated rejection base biomarker discovery biomarker validation clinically relevant cohort comorbidity cost data registry diagnostic biomarker diagnostic signature exome sequencing genetic architecture genetic variant genome wide association study genome-wide heart allograft high risk immunoreaction improved improved outcome insight metabolomics minimally invasive molecular marker multiple omics novel novel diagnostics patient population post-transplant precision medicine prevent prognostic prognostic signature prognostication prospective protein metabolite standard of care study population tool transcriptome transcriptome sequencing transcriptomics

项目摘要

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.

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。