The Impact of Oxidative Stress on Erythocyte Biology

氧化应激对红细胞生物学的影响

基本信息

批准号：
10022515
负责人：
Angelo D'Alessandro
金额：
$ 222.52万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022515
关键词：
Acute Affect Age American Animal Model Animals Biochemical Biological Products Biology Blood Blood Banks Blood Group Antigens Bone Marrow Cell membrane Cell physiology Cellular biology Chronic Clinical Investigator Collaborations Consensus Consumption Data Defect Diet Disease Eicosanoids Environment Environmental Risk Factor Epigenetic Process Erythrocyte Transfusion Erythrocytes Ethics Fatty Acids Generations Genetic Germination Goals Hand Hemorrhage Hemostatic function Hour Human Human Biology Human Experimentation Human Volunteers Hydroxyeicosatetraenoic Acids Immune response Immunology In Vitro Injury Iron Label Lesion Life Link Lipid Biochemistry Lipids Measures Metabolism Methods Modeling Molecular Biology Mouse Strains Mus National Heart, Lung, and Blood Institute Oxidative Stress Pathway interactions Patients Preparation Production Productivity Recovery Research Resolution Role Savings Science Scientist Sickle Cell Anemia Site Standardization Talents Testing Therapeutic Intervention Transfusion Translating base blood lipid clinical practice design improved in vivo innovation insight lipid metabolism metabolomics mouse model multidisciplinary novel nutrition oxidant stress oxidation precision medicine predictive marker response six transmembrane epithelial antigen of the prostate 3 success symposium theories transfusion medicine

项目摘要

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.

这个多站点的多PI提案的目的是获得对遗传和遗传的机械理解涉及红细胞（RBC）处理氧化应激的能力的环境因素。 RBC 输血是住院患者最常见的热干预措施。但是，有 RBCS在转移后如何循环和功能的大量供体对供体变异性。有由于需要这种寿命的各种疾病，接受者对输血的反应的差异类似 - 保存疗法。我们使用小鼠模型的初步数据，与人类研究链接并随后链接，表明，尤其是脂质代谢，尤其是类花生酸的产生，可以预测RBC的质量。我们还确定了一种新型的酶促途径（即STEAP3）负责确定RBC的存储质量各种小鼠菌株。最后，我们确定了饮食（铁酸和脂肪酸消耗）的新作用修饰RBC膜中的脂质氧化并影响RBC质量。这些发现一起导致了我们氧化物应激及其因素影响它的中心假设是RBC存储的关键决定剂质量。该提案代表了具有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，“ OMICS”方法以及RBC和脂质生物化学的目的是提高我们对RBC质量的遗传和环境确定的理解。在AIM＃1中，我们将阐明氧化应激影响RBC的供体和受体遗传和环境因素在鼠标模型中输血。在AIM＃2中，我们将确定小鼠的哪些结果可以翻译成人类设置并将在人类中提供机械细节。镰状细胞中氧化升高的影响也将直接检查有关输血的RBC生物学的疾病接受者。该提议是旨在在目标之间提供动态的交叉循环，从而允许迭代和持续的机械研究，简单地探索了优势并减轻动物和人类研究的弱点，分别。这项研究将导致创新且非常可以翻译的方法来改善输血疗法将增强对RBC氧化应力处理的基本机械理解。