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

 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，同种异体移植排斥反应经常发生，并破坏了移植的益处。排异监测目前依赖于预测能力有限的侵入性活检程序。最近的发现是，供体来源的DNA在移植物损伤的情况下在受体的循环中释放，这为非侵入性的、基于基因组学的移植监测方法开辟了可能性。使用DNA测序方法分析游离DNA，这组研究人员最近观察到肺移植患者血浆中存在供体来源的线粒体游离DNA。线粒体DNA尚未被研究作为实体器官移植中急性排斥反应的标志物，但提供了几个诊断优势：线粒体DNA在每个细胞中存在大量，因此在血浆中丰富，供体和受体线粒体序列可以相对容易地区分。研究游离线粒体DNA作为移植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。可以想象的是，伴随移植物损伤的线粒体DNA的释放促进了在实体器官移植中观察到的许多有害的免疫反应，但这种关系实际上尚未研究。将研究游离线粒体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，重点是心脏和肺移植患者。该项目将使用通过先前研究获得的库存样品和新收集的样品的组合来完成。该提案的成功实施将通过为敏感和可靠的移植监测开辟新的途径，直接和积极地影响患者护理。

 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.