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

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

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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（适用提供）：器官移植是许多终阶段器官疾病的首选治疗方法。但是，同类抑制经常发生，并使移植的益处降低了。拒绝监测当前依赖于具有有限预测能力的侵入性活检程序。最近发现，在接枝损伤的情况下，在接受者的循环中释放了供体衍生的DNA，这为非侵入性，基于基因组学的方法提供了用于移植监测的方法。使用DNA测序方法在无细胞DNA的分析中，该研究人员最近观察到在肺移植患者血浆中存在供体衍生的线粒体无细胞DNA。线粒体DNA尚未被研究为固体器官移植中急性排斥的标志，但具有多种诊断优势：在每个细胞中，线粒体DNA都有很高的呈现，因此，在等离子体中是一个全面的，并且在供体和受益的线粒体序列中可以很好地区分和相互区分。研究无细胞线粒体DNA作为急性排斥在移植中的标志的另一个重要动机是线粒体DNA在排斥发病机理中的潜在作用。线粒体DNA是一种强大的“损伤”相关分子模式（DAMP），这是一种内源性分子，在细胞损伤期间释放时可以激活先天免疫。可以想象的是，涉及谷物损伤的线粒体DNA的释放会促进在固体器官移植中观察到的许多有害免疫反应，但这种关系实际上仍然没有研究。无细胞线粒体DNA作为急性排斥的标志及其作为器官移植的潮湿的作用的潜力将被研究，重点关注心脏和肺移植患者。该项目将使用以前的研究以及新收集的样品的组合来完成。该提案的成功实施将直接和积极地影响患者护理，以开放新的途径，以进行敏感和可靠的移植监测。