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Mitochondrial Cell-Free DNA as a Marker of Rejection and Damage-Associated Molecular Pattern in Organ Transplantation

线粒体游离 DNA 作为器官移植中排斥和损伤相关分子模式的标记

基本信息

批准号：
9335715
负责人：
Iwijn De Vlaminck
金额：
$ 19.4万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-20 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335715
关键词：
Acute Address Bacterial DNA Bioinformatics Biological Markers Biopsy Blood Blood Circulation Cells Complex DNA DNA sequencing Diagnosis Diagnostic Disease Event Genome Genomics Goals Heart Transplantation Heart-Lung Transplantation Immune response Inflammation Injury Lung Transplantation Methodology Mitochondria Mitochondrial DNA Molecular Monitor Motivation Natural Immunity Operative Surgical Procedures Organ Organ Transplantation Pathogenesis Patient Care Patients Pattern Performance Plasma Procedures Property Prospective Studies Protocols documentation Reperfusion Injury Research Personnel Role SNP genotyping Sampling Shotgun Sequencing Solid System Testing Transplant Recipients Transplantation Variant allograft rejection base cell free DNA cell injury circulating DNA cohort diagnostic biomarker mitochondrial genome new therapeutic target noninvasive diagnosis public health relevance virtual whole genome

项目摘要

DESCRIPTION (provided by applicant): Organ transplantation is the preferred treatment for many end-stage organ diseases. Allograft rejection however occurs frequently and undermines the benefits of transplantation. Rejection monitoring currently relies on invasive biopsy procedures with limited predictive power. The recent discovery that donor-derived DNA is released in the recipient's circulation in the event of graft injury opens the possibility of non-invasive, genomics-based methodologies for transplant monitoring. Using DNA sequencing approaches in the analysis of cell-free DNA, this team of researchers has recently observed the presence of donor derived mitochondrial cell-free DNA in plasma of lung transplant patients. Mitochondrial DNA has not been investigated as a marker of acute rejection in solid-organ transplantation, but offers several diagnostic advantages: mitochondrial DNA is present in high numbers in every cell, and is consequently abundant in plasma, and donor and recipient mitochondrial sequences can be distinguished relatively easily. A further important motivation for investigating cell-free mitochondrial DNA as a marker of acute rejection in transplantation is the potential role of mitochondrial DNA in rejection pathogenesis. Mitochondrial DNA is a powerful `damage'-associated molecular pattern (DAMP), an endogenous molecule that can activate innate immunity when released during cellular injury. It is conceivable that the release of mitochondrial DNA that accompanies graft injury promotes many of the harmful immunologic responses observed in solid-organ transplantation, but this relationship remains virtually unstudied. The potential of cell-free mitochondrial DNA as a marker of acute rejection and its role as a DAMP in organ transplantation will be investigated, focusing on heart and lung transplant patients. The project will be accomplished using a combination of banked samples, available through a previous study, and newly collected samples. Successful implementation of this proposal will directly and positively impact patient care by opening new avenues for sensitive and reliable transplant monitoring.

描述（由申请人提供）：器官移植是许多终末期器官疾病的首选治疗方法。然而，同种异体移植排斥经常发生并损害了移植的益处。目前，排斥监测依赖于预测能力有限的侵入性活检程序。最近发现，在移植物损伤时，供体来源的 DNA 会释放到受体循环中，这为非侵入性、基于基因组学的移植监测方法提供了可能性。该研究小组最近利用 DNA 测序方法分析无细胞 DNA，观察到肺移植患者血浆中存在供体来源的线粒体无细胞 DNA。线粒体 DNA 尚未被研究为实体器官移植中急性排斥反应的标志物，但具有多种诊断优势：线粒体 DNA 在每个细胞中大量存在，因此在血浆中含量丰富，并且可以相对容易地区分供体和受体线粒体序列。研究无细胞线粒体 DNA 作为移植中急性排斥反应标志物的另一个重要动机是线粒体 DNA 在排斥发病机制中的潜在作用。线粒体 DNA 是一种强大的“损伤”相关分子模式 (DAMP)，是一种内源性分子，在细胞损伤期间释放时可以激活先天免疫。可以想象，伴随移植物损伤的线粒体DNA的释放促进了实体器官移植中观察到的许多有害的免疫反应，但这种关系实际上仍未得到研究。将研究无细胞线粒体 DNA 作为急性排斥反应标志物的潜力及其在器官移植中作为 DAMP 的作用，重点关注心脏和肺移植患者。该项目将结合使用先前研究中获得的银行样本和新收集的样本来完成。该提案的成功实施将为敏感和可靠的移植监测开辟新途径，从而直接和积极地影响患者护理。