The Impact of Oxidative Stress on Erythocyte Biology

这个多位点、多PI提案的目标是获得对遗传和 控制红细胞（RBC）处理氧化应激能力的环境因素。RBC 输血是住院患者最常见的治疗干预;然而， 在输血后RBC如何储存、循环和发挥功能方面，供体与供体之间存在很大的差异。有 由于需要这种生命的广泛疾病，受体对输血的反应也存在类似的变异性- 拯救治疗我们使用小鼠模型的初步数据，与人类研究相关联， 表明脂质代谢，一般来说，特别是类花生酸的产生，预测RBC质量。我们 还鉴定了一种新的酶途径（即，步骤3）负责确定 各种小鼠品系。最后，我们确定了饮食（铁和脂肪酸摄入）在 改变RBC膜中的脂质氧化并影响RBC质量。总之，这些发现导致我们 中心假设氧化应激及其影响因素是红细胞储存的关键决定因素 质量. 该提案代表了具有不同输血专业知识的科学家的多机构合作 生物学、小鼠模型、人类研究、“组学”方法以及RBC和脂质生物化学，旨在 提高我们对RBC质量的遗传和环境决定因素的理解。因此，在目标#1中，我们将 阐明供体和受体的遗传和环境因素，氧化应激影响红细胞 小鼠模型中的输血。在目标#2中，我们将确定小鼠中的哪些结果可转化为人类 设置并将提供人体的机械细节。氧化应激对镰状细胞的影响 还将直接检查疾病接受者对输注红细胞生物学的影响。这项建议是 旨在提供目标之间的动态交叉发芽，允许迭代和持续的机制 同时利用动物和人类研究的优势并减轻其弱点的研究， 分别这项研究将导致创新和突出的可翻译的方法，以改善 输血治疗，并将提高红细胞氧化应激处理的基本机制的理解。

The goal of this multi-site, multi-PI proposal is to gain a mechanistic understanding of the genetic and environmental factors governing the ability of red blood cells (RBCs) to handle oxidative stress. RBC transfusion is the single most common therapeutic intervention for hospitalized patients; however, there is substantial donor-to-donor variability in how RBCs store, circulate, and function post-transfusion. There is similar variability in recipient responses to transfusion, due to the wide range of diseases requiring this life- saving therapy. Our preliminary data using mouse models, linked to and followed by human studies, demonstrate that lipid metabolism, in general, and eicosanoid generation, in particular, predict RBC quality. We also identified a novel enzymatic pathway (i.e., Steap3) responsible for determining RBC storage quality of various mouse strains. Finally, we identified a novel role for diet (both iron and fatty acid consumption) in modifying lipid oxidation in RBC membranes and affecting RBC quality. Together, these findings led to our central hypothesis that oxidant stress, and factors influencing it, is a critical determinant of RBC storage quality. This proposal represents a multi-institutional collaboration of scientists with diverse expertise in transfusion biology, mouse models, human studies, “omics” approaches, and RBC and lipid biochemistry, aimed to improve our understanding of genetic and environmental determinants of RBC quality. Thus, in Aim #1, we will elucidate donor and recipient genetic and environmental factors by which oxidant stress affects RBC transfusion in mouse models. In Aim #2, we will identify which results in mice are translatable to the human setting and will provide mechanistic details in humans. The effects of elevated oxidant stress in sickle cell disease recipients on the biology of the transfused RBCs will also be directly examined. This proposal is designed to provide dynamic cross-germination between Aims, allowing for iterative and ongoing mechanistic studies, which simultaneously exploit the strengths and mitigate the weaknesses of animal and human studies, respectively. This research will lead to innovative and eminently translatable approaches for improving transfusion therapy and will enhance basic mechanistic understanding of RBC oxidant stress handling.