The Impact of Oxidative Stress on Erythocyte Biology

这个多部位、多PI方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。红细胞 输血是住院患者最常见的单一治疗措施；然而，有 输血后红细胞的储存、循环和功能在供者与供者之间存在很大的变异性。的确有 受者对输血的反应也有类似的差异，因为需要这种生命的疾病范围很广- 拯救疗法。我们使用小鼠模型的初步数据，与人类研究相关联，并随后进行， 证明一般情况下，脂类代谢和二十烷类化合物的生成可以预测RBC的质量。我们 还鉴定了一种新的酶途径(即Steap3)，它负责决定红血球的储存质量 不同的老鼠品系。最后，我们确定了饮食(铁和脂肪酸的消耗)在 改善红细胞膜的脂质氧化，影响红细胞膜的质量。总之，这些发现导致了我们的 氧化应激及其影响因素是红细胞储存的关键决定因素的中心假设 质量。 这项提议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、人体研究、“组学”方法，以及红细胞和脂质生物化学，旨在 提高我们对红细胞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 阐明氧化应激影响红细胞的供受者遗传和环境因素 在小鼠模型中输血。在目标2中，我们将确定在小鼠身上哪些结果是可以翻译给人类的 并将提供人体的机械细节。氧化应激升高对镰状细胞的影响 疾病接受者也将接受关于输注红细胞生物学的直接检查。这项建议是 旨在提供目标之间的动态交叉萌发，允许迭代和持续的机制 同时利用动物和人类研究的长处和弱项的研究， 分别进行了分析。这项研究将导致创新的和卓越的可译性方法，以改善 输血疗法，并将加强对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.