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。输血是住院患者最常见的治疗干预措施；然而，输血后红细胞的储存、检修和功能存在很大差异。由于需要这种生命的多种疾病，受血者对输血的反应也存在类似的变异性我们使用小鼠模型获得的初步数据与人体研究相关并随后进行，证明脂质代谢，特别是类二十烷酸的生成，可以预测红细胞质量。还确定了一种新的酶途径（即 Steap3），负责确定红细胞储存质量最后，我们确定了饮食（铁和脂肪酸消耗）在其中的新作用。改变红细胞膜中的脂质氧化并影响红细胞质量，这些发现共同得出了我们的结论。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体和受体遗传和环境因素在小鼠模型中的输血在目标#2中，我们将确定小鼠的哪些结果可以转化为人类。设置并将提供人类镰状细胞中氧化应激升高的影响的机制细节。疾病接受者对输血红细胞的生物学特性也将进行直接检查。旨在提供目标之间的动态交叉萌芽，允许迭代和持续的机制研究，同时利用动物和人类研究的优点并弥补其缺点，这项研究将带来创新且可转化的改进方法。输血疗法并将增强对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.