Improving red blood cell transfusion through systems biology

 说明(由申请人提供)：储存在经批准的添加剂溶液中的红细胞(RBC)经历一系列新陈代谢和物理化学变化，称为“储存损伤”，降低了旧输注红细胞单位的有效性和安全性。尽管储存损伤的后果正在慢慢得到很好的证明，但在开发红细胞输注质量和安全的新技术方面进展缓慢的一个主要原因是缺乏对储存过程中代谢下降的全球了解。人们一直有兴趣利用高通量代谢物图谱来在全球范围内了解红细胞代谢下降，但对复杂数据集的数据分析一直是一个艰巨的挑战。在该计划的第一阶段，我们开发了第一个强大的计算平台，涉及统计分析、代谢网络的系统生物学和数据驱动的动力学模型，以在完整的网络环境中全面解释和分析RBC代谢物图谱。利用时间进程全球定量代谢物图谱，我们确定红细胞经历了临床上相关的非线性衰退过程，并通过计算确定了驱动这一衰退过程的关键代谢酶。基于计算结果，我们设计了两种新的加法溶液策略来缓解衰变过程，提高红细胞输注的安全性和准确性。在这项提案中，我们将通过1)代谢组学实验和2)包括细胞流变学和微粒生成在内的非代谢红细胞生理学实验来验证通过计算确定的添加剂解决方案在缓解非线性衰退过程中的有效性。一个成功的添加剂溶液将被推进到介质精制和临床前测试。

 DESCRIPTION (provided by applicant): Red blood cells (RBC) stored in approved additive solutions undergo a set of metabolic and physicochemical changes referred to as `storage lesions' reducing the efficacy and safety of older transfused RBC units. Though the consequences of the storage lesion are slowly becoming well documented, a major reason for delayed progress in developing new technologies for quality and safety of RBC transfusion is the lack of global understanding of metabolic decline during storage. There has been interest to utilize high-throughput metabolite profiling for global understanding of RBC 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, systems biology of metabolic networks, and data-driven kinetic models to fully interpret and analyze RBC metabolite-profiles in a complete network context. Using time-course global, quantitative metabolite profiling, we determined that RBCs undergo a clinically relevant non-linear decay process and computationally identified key metabolic enzymes that drive this decay process. Based on the computational results, we have devised two novel additive solution strategies to mitigate the decay process and improve the safety and accuracy of RBC transfusion. In this 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 RBC physiology experiments including cell rheology and microparticle generation. A successful additive solution will be progressed to media refinement and preclinical testing.