Improving safety and efficacy of platelet transfusion through systems biology

项目摘要 血小板输注对于严重出血的患者至关重要， 美国和欧洲每年。在美国，血小板通常储存5天， 浪费了20%的供应。储存时间短是细菌污染和血小板减少的结果。 质量考虑。尽管已经开发了许多用于细菌测试和病原体检测的方法， 然而，由于血小板的灭活，很少有人开发用于改善储存的血小板的质量。血小板添加剂溶液 有可能提高储存质量和持续时间，减少血浆相关的过敏反应， 病原体减少技术的功效，并节省血浆，然后可以用作额外的 输血产品。虽然好处是众所周知的，但在开发新的 用于提高血小板输注的质量和安全性的血小板添加剂溶液， 对储存过程中的生物化学和信号变化有广泛的了解。有兴趣利用 高通量代谢物分析用于全面了解血小板代谢下降， 复杂的数据集一直是一个艰巨的挑战。在这个项目的第一阶段，我们开发了第一个强大的 涉及代谢和信号网络的统计分析和系统生物学的计算平台 在完整的网络环境中解释和分析PLT代谢组学和蛋白质组学特征。利用时间- 通过全球定量代谢物分析，我们确定PLT经历非线性衰减过程 并通过计算确定了驱动这种衰变的关键代谢酶和细胞过程。基于 计算结果，我们设计了两种新的加法解决方案的战略，以减轻衰减过程 并提高PLT单元的长度。在第二阶段的提案中，我们将验证计算确定的 通过1）代谢组学实验， 和2）非代谢性PLT生理学实验，包括细胞活化和止血有效性。一 成功添加剂溶液将进展到培养基精制和临床前测试。

Project Summary Platelet transfusion is critical for severely bleeding patients and nearly 6 million units are transfused in the United States and Europe annually. In the United States, platelets are typically stored for 5 days resulting in a waste of 20% of their supply. Short storage duration is a consequence of bacterial contamination and platelet quality considerations. Though many methods have been developed for bacterial testing and pathogen inactivation, fewer have been developed for improving quality of stored platelets. Platelet additive solutions have the possibility to increase storage quality and duration, reduce plasma-related allergic reactions, impact the efficacy of pathogen reduction techniques, and save plasma which can then be used as an additional transfusion product. While the benefits are well known, there has been little progress in developing new platelet additive solutions for increasing quality and safety of platelet transfusion because there is a lack of broad understanding of biochemical and signaling changes during storage. There has been interest to utilize high-throughput metabolite profiling for global understanding of platelet metabolic decline but data analysis of complex datasets has been a daunting challenge. In Phase I of this program, we developed the first, robust computational platform involving statistical analysis and systems biology of metabolic and signaling networks to interpret and analyze PLT metabolomic and proteomic profiles in a complete network context. Using time- course global, quantitative metabolite profiling, we determined that PLTs undergo a non-linear decay process and computationally identified key metabolic enzymes and cellular process that drive this decay. Based on the computational results, we have devised two novel additive solution strategies to mitigate the decay process and improve the length of PLT units. In this Phase II proposal, we will validate the computationally determined additive solutions for efficacy in alleviating the non-linear decay process through 1) metabolomics experiments, and 2) non-metabolic PLT physiology experiments including cell activation and hemostatic effectiveness. A successful additive solution will be progressed to media refinement and preclinical testing.