Improving red blood cell transfusion through systems biology

通过系统生物学改善红细胞输注

• 批准号: 9049084
• 负责人: Aarash Bordbar
• 金额: $ 102.93万
• 依托单位: SINOPIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-19 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049084
• 关键词: Accounting; Affect; Algorithms; Area; Biochemical Pathway; Biological Preservation; Blood Banks; Caring; Cell physiology; Cells; Cellular Metabolic Process; Cellular Morphology; Clinical; Complex; Computational Technique; Computer Simulation; Computing Methodologies; Data; Data Analyses; Data Set; Effectiveness; Enzymes; Erythrocyte Transfusion; Erythrocytes; Formulation; Generations; Hospital Costs; Hospitalization; Hospitals; In Vitro; Intervention; Kinetics; Lesion; Life; Measures; Medicine; Metabolic; Metabolic Pathway; Methods; Modeling; Morbidity - disease rate; Observational Study; Outcome; Patient-Focused Outcomes; Patients; Phase; Preclinical Testing; Process; Publishing; Randomized Clinical Trials; Reaction; Records; Rheology; Safety; Staging; Statistical Data Interpretation; Supplementation; Systems Biology; Techniques; Technology; Testing; Transfusion; United States; Update; Validation; Work; base; clinically relevant; commercialization; cost; improved; interest; metabolic profile; metabolomics; model design; new technology; novel; open innovation; prevent; product development; programs; public health relevance; research study; statistics; success; time use

 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.

 描述（由申请人提供）：储存在批准的添加剂溶液中的红细胞（RBC）发生一系列代谢和理化变化，称为“储存损伤”，降低了旧输注RBC单位的有效性和安全性。尽管储存损伤的后果慢慢得到了很好的记录，但红细胞输注质量和安全性新技术开发进展缓慢的一个主要原因是缺乏对储存期间代谢下降的全面了解。人们一直有兴趣利用高通量代谢物分析来全面了解RBC代谢下降，但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代谢谱。使用时程全局定量代谢物分析，我们确定RBC经历临床相关的非线性衰变过程，并通过计算确定了驱动该衰变过程的关键代谢酶。基于计算结果，我们设计了两种新的添加剂解决方案，以减轻衰变过程，提高红细胞输注的安全性和准确性。在本提案中，我们将通过1）代谢组学实验和2）非代谢RBC生理学实验（包括细胞流变学和微粒生成）验证计算确定的添加剂解决方案在缓解非线性衰减过程中的功效。一个成功的添加剂解决方案将进展到媒体细化和临床前测试。