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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：
10487440
负责人：
Angelo D'Alessandro
金额：
$ 223.49万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10487440
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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Low-Dose Dietary Fish Oil Improves RBC Deformability without Improving Post-Transfusion Recovery in Mice.

DOI：
10.3390/nu15204456
发表时间：
2023-10-20
期刊：
Nutrients
影响因子：
5.9
作者：
Kim CY;Larsen HJ;Spitalnik SL;Hod EA;Francis RO;Hudson KE;Gordy DE;Stone EF;Peltier S;Amireault P;D'Alessandro A;Zimring JC;Buehler PW;Fu X;Thomas T
通讯作者：
Thomas T

Storage-Induced Micro-Erythrocytes Can Be Quantified and Sorted by Flow Cytometry.

DOI：
10.3389/fphys.2022.838138
发表时间：
2022
期刊：
Frontiers in physiology
影响因子：
4
作者：
Marin M;Peltier S;Hadjou Y;Georgeault S;Dussiot M;Roussel C;Hermine O;Roingeard P;Buffet PA;Amireault P
通讯作者：
Amireault P

Reticulocytes in donor blood units enhance red blood cell alloimmunization.

DOI：
10.3324/haematol.2023.282815
发表时间：
2023-10-01
期刊：
HAEMATOLOGICA
影响因子：
10.1
作者：
Thomas, Tiffany A.;Qiu, Annie;Kim, Christopher Y.;Gordy, Dominique E.;Miller, Anabel;Tredicine, Maria;Dzieciatkowska, Monika;Dei Zotti, Flavia;Hod, Eldad A.;D'Alessandro, Angelo;Zimring, James C.;Spitalnik, Steven L.;Hudson, Krystalyn E.
通讯作者：
Hudson, Krystalyn E.