Improving safety and efficacy of platelet transfusion through systems biology

 描述(申请人提供)：血小板输注对于严重出血的患者是至关重要的，在美国和欧洲每年有近700万个单位被输注。在美国，血小板只能储存5天，导致其供应的15%被浪费。储存时间短是细菌污染和血小板质量考虑的结果。虽然已经开发了许多用于细菌检测和病原体灭活的方法，但用于提高储存的血小板质量的方法很少。血小板添加剂溶液有可能提高储存质量和持续时间，减少与血浆相关的过敏反应，影响病原体减少技术的效果，并节省血浆，然后作为额外的输血产品使用。虽然好处是众所周知的，但由于缺乏对储存过程中生化下降的广泛了解，因此在开发新的血小板添加剂溶液以提高血小板输注的质量和安全性方面进展甚微。人们有兴趣利用高通量代谢物和蛋白质图谱在全球范围内了解血小板代谢下降，但对复杂数据集的数据分析一直是一个艰巨的挑战。拟议的计划将开发第一个强大的计算平台，涉及统计分析、系统生物学和 代谢和信号网络，以及数据驱动的动力学模型，在完整的网络环境中全面解释和分析血小板代谢物和蛋白质谱。该计划将利用最近产生的时间进程全球定量代谢物图谱来跟踪细胞内和 标准储存条件下的细胞外血小板代谢物和现有的蛋白质组学研究。所获得的深入的生化理解将被用于基于生物功效、成本和调节器障碍来定量预测最佳添加剂解决方案。在第二阶段，将选择预测的添加剂进行实验验证和测试。

 DESCRIPTION (provided by applicant): Platelet transfusion is critical for severely bleeding patients and nearly 7 million units are transfused in the United States and Europe annually. In the United States, platelets can only be stored for 5 days resulting in a waste of 15% 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 decline during storage. There has been interest to utilize high-throughput metabolite and protein profiling for global understanding of platelet metabolic decline but data analysis of complex datasets has been a daunting challenge. The proposed program will develop the first, robust computational platform involving statistical analysis, systems biology of metabolic and signaling networks, and data-driven kinetic models to fully interpret and analyze platelet metabolite and protein profiles in a complete network context. The program will utilize recently generated time-course global, quantitative metabolite profiling to track intracellular and extracellular platelet metabolites under standard storage conditions and available proteomic studies in literature. The deep biochemical understanding obtained will be employed to quantitatively predict optimal additive solutions based on biological efficacy, cost, and regulator hurdles. Predicted additives will be chosen for experimental validation and testing in Phase II.