Serious Hazards of Transfusion & Cellular Therapies: Mechanisms and Intervention

描述(申请人提供)：本项目资助申请(P01)是对现有资助的更新：解决输血和细胞疗法的严重危险的机制和干预措施。该计划代表了埃默里大学输血和细胞治疗中心(CTCT)的综合努力，该中心包括一组医生和科学家，他们致力于通过基础、转化和临床研究、卓越的临床护理和教学以及未来领导者和科学家的教育来推动输血医学和细胞治疗领域的进步。调查人员感谢目前的6年资助期使我们能够改善我们的协同互动，并在以前资助的调查中取得重大进展。此外，我们认为，这一续签申请代表了一系列相互关联的项目的显著改进。这一P01更新的中心主题已被修改，使项目之间更加一致，允许更多的跨项目互动和调查人员之间的协同。我们仍然致力于“输血的严重危险”，但我们的重点是输注在输血前储存了较长时间的红细胞(这里称为储存期红细胞[saRBCs])后，受血者发生的那些危险。这些危险包括成人受者的红细胞存活期缩短和NO介导的血管反应性改变(项目1)、新生儿患者的坏死性小肠结肠炎(项目2)、移植患者的同种异体免疫反应性改变(项目3)和红细胞存活率缩短(项目4)。该计划项目的主要目标是开发一组红细胞生物标志物，以识别已进入功能受损状态的红细胞，这种状态不仅使这些细胞易于降低输血后存活率，还会导致输血接受者的不良反应。虽然目前的证据支持这样的观点，即红细胞储存的时间越长，它们的效果就越差，导致不良事件的可能性就越大，但我们认为，基于时间储存年限的简单化表述最终会适得其反。相反，通过利用生物标记物来测试红细胞单位的“代谢年龄”，可以提高输血的有效性和安全性。

DESCRIPTION (provided by applicant): This program project grant (P01) application is a renewal of the current grant: Mechanisms and Interventions Addressing Serious Hazards of Transfusion and Cellular Therapies. This Program represents an integrative endeavor by the Emory University Center for Transfusion and Cellular Therapies (CTCT) which includes a group of physician-scientists dedicated to the advancement of the field of transfusion medicine and cellular therapies via basic, translational and clinical research, excellence in clinical care and teaching, and the education of future leaders and scientists. The investigators are grateful that the current 6 year funding period has allowed us to improve our synergistic interactions and make significant progress in the previously funded investigations. Furthermore, we believe that this renewal application represents a significantly improved set of interrelated projects. The central theme of this P01 renewal has been modified to be more consistent between projects, allowing greater cross-project interactions and synergy between investigators. We still address "Serious Hazards of Transfusion", but our focus is on those hazards that occur in transfusion recipients following infusion of RBCs that have been stored for extended periods of time prior to transfusion (herein called storage-aged RBC [saRBCs]). These hazards include shortened RBC survival and alterations in NO-mediated vaso-responsiveness in adult recipients (Project 1), necrotizing enterocolitis (NEC) in neonatal patients (Project 2), altered alloimmune responsiveness in transplant patients (Project 3), and shortened RBC survival (Project 4). The primary goal of the Projects in this Program is to develop a panel of RBC biomarkers that identify RBCs that have entered a state of impaired functionality that not only predisposes these cells to reduced post-transfusion survival but leads to adverse effects in the transfusion recipient. While current evidence supports the contention that generally the longer RBCs are stored the less efficacious they will be and the more likely they are to cause adverse events, we believe that a simplistic formulation based on chronological storage age is ultimately counter-productive. Rather, transfusion efficacy and safety can be improved by utilizing biomarkers to test for the "metabolic age" of RBC units.