Adverse effects of RBC transfusions: A unifying hypothesis

红细胞输注的不良反应：统一假设

• 批准号: 8818172
• 负责人: John D Roback
• 金额: $ 87.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818172
• 关键词: Address; Adverse effects; Affect; Allogenic; Animals; Backcrossings; Biological Markers; Biology; Blood; Blood Banks; Blood Screening; Blood Transfusion; Blood Vessels; Blood donor; Breeding; Canis familiaris; Cell Survival; Cell physiology; Characteristics; Chromosomes, Human, Pair 1; Clinical; Clinical Research; Complex; Data; Defect; Development; Eicosanoids; Enzymes; Erythrocyte Transfusion; Erythrocytes; Etiology; Event; Funding; Generations; Genetic; Genetic Determinism; Genetic Markers; Genotype; Goals; Grant; Hospitals; Hour; Human; In Vitro; Investigation; Knowledge; Lead; Lesion; Link; Longevity; Measures; Mediating; Membrane; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolism; Methodology; Methods; Modeling; Modification; Morbidity - disease rate; Mus; Outcome; Patients; Pattern; Phenotype; Physiological; Poison; Prospective Studies; Quantitative Trait Loci; Recovery; Regulation; Research; Research Personnel; Safety; Sampling; Science; Source; Techniques; Testing; Therapeutic procedure; Time; Transfusion; Validation; Vascular blood supply; Vasodilation; Work; aged; base; congenic breeding; experience; functional disability; genetic element; genetic pedigree; genome wide association study; improved; in vivo; interest; irradiation; metabolomics; mortality; mouse model; novel; prevent; public health relevance; repository; research study; screening; tool

DESCRIPTION (provided by applicant): Transfusion of red blood cells (RBCs), the most common therapeutic procedure performed in US hospitals, is usually effective at preventing morbidity and mortality in anemic patients. However, recent studies indicate that some RBC units have functional defects that impair their efficacy and may actually cause harm to transfused patients. These defects, which appear to increase the longer RBC units are stored prior to transfusion, have been called "RBC storage lesions". Transfusion of RBC units with storage lesions may adversely affect thousands of patients annually, but at present we have no accurate methods to identify such units. During the previous funding period for this R01 grant, we observed unexpected donor-to-donor variability in RBC metabolism during blood bank storage. Based on these data, we propose to identify specific metabolic (human RBCs) and genetic (murine RBCs) biomarkers that not only reflect the underlying differences in RBC function due to storage time and/or donor factors, but also can be used clinically to predict which RBC units may cause adverse post-transfusion events, allowing them to be removed from the blood supply before transfusion. To provide the most powerful approach to achieve this goal, we propose an integrated research effort that combines (1) the relevancy of donor/recipient-based human RBC transfusion investigations, with (2) the mechanistic power of mouse models. The human studies will utilize methodologies we have developed to identify metabolic biomarkers that predict RBC function, post-transfusion RBC survival, and vascular effects. The advantages of mouse studies include finely characterized genetics, rapid breeding times, ease of generating complex pedigrees, and the power of phenotype-genotype analysis. These advantages will be exploited by performing GWAS to identify genetic markers for mouse RBC storage phenotypes, and then selectively backcrossing to establish causality between selected genetic elements and phenotypes of interest. The proposed coordinated investigations allow each model to be used for its unique strengths, while compensating for intrinsic weaknesses, and thus provides efficient cross- validation of selected biomarkers. These studies will extend work started during the previous funding period, and will lead to the validation of RBC biomarkers that we believe will identify RBC units most likely to cause adverse recipient effects, allowing them to be sequestered prior to transfusion.

描述（由申请人提供）：美国医院中最常见的治疗方法的红细胞（RBC）通常可以有效预防贫血患者的发病率和死亡率。但是，最近的研究表明，某些RBC单元具有功能缺陷，可损害其功效，实际上可能对被输血的患者造成伤害。这些缺陷似乎增加了较长的RBC单元在输血之前存储，称为“ RBC存储病变”。带有储存病变的RBC单元的输血可能每年对数千名患者产生不利影响，但目前我们没有准确的方法来识别此类单位。在此R01赠款的前几个资金期间，我们观察到血库存储期间RBC代谢的意外供体对唐纳尔变异性。基于这些数据，我们建议确定特定的代谢（人RBC）和遗传（鼠RBC）生物标志物，这些标志物不仅反映了由于存储时间和/或供体因素而导致的RBC功能的潜在差异，还可以在临床上使用哪些RBC单位来预测哪些RBC单位可能会导致不良后传递事件，从而使它们可以转移到血液中。为了提供最有力的方法来实现这一目标，我们提出了一项集成的研究工作，将基于捐赠者/受体的人类RBC输血研究的相关性与（2）小鼠模型的机械力量相结合。人类研究将利用我们开发的方法来鉴定预测RBC功能，转移后RBC存活和血管作用的代谢生物标志物。小鼠研究的优势包括精细的遗传学，快速繁殖时间，易于产生复杂的谱系以及表型基因型分析的力量。这些优点将通过执行GWAS来鉴定小鼠RBC存储表型的遗传标记，然后选择性地进行跨性，以确定所选遗传元件和感兴趣的表型之间建立因果关系，从而利用这些优点。提出的协调研究允许每个模型用于其独特的优势，同时补偿内在的弱点，从而提供了有效的选择生物标志物的交叉验证。这些研究将延长上一个融资期内开始的工作，并将导致RBC生物标志物的验证，我们认为这将确定最有可能引起不良受体效应的RBC单位，从而使它们在输血之前被隔离。