Effect of blood donor sex and testosterone on predisposition to hemolysis in stored red blood cells

献血者性别和睾酮对储存红细胞溶血倾向的影响

基本信息

批准号：
10322992
负责人：
Tamir Kanias
金额：
$ 38.52万
依托单位：
VITALANT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-09-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322992
关键词：
Affect Age American Androgens Anions Apoptosis Attenuated Binding Biological Biological Factors Biology Blood Banks Blood Circulation Blood Donations Blood Transfusion Blood donor Candidate Disease Gene Cell Differentiation process Cell Line Cell Survival Cell physiology Cellular Structures Cellular biology Characteristics Code Cryopreservation Databases Disease Erythrocyte Transfusion Erythrocytes Erythroid Cells Erythropoiesis Exhibits Gene Expression Genes Genetic Genetic Databases Genetic Predisposition to Disease Genomics Goals Guidelines Hemolysis Human Human Genome Knock-out MAP Kinase Gene Maps Mediating Mediator of activation protein Medical Membrane Modeling Molecular Monitor Mouse Strains Mus National Heart, Lung, and Blood Institute Orchiectomy Osmotic Shocks Outcome Ovariectomy Oxidative Stress Patients Pharmaceutical Preparations Phosphotransferases Polycythemia Population Heterogeneity Population Study Predisposition Race Recovery Risk Risk Assessment Safety Sex Differences Signal Pathway Signal Transduction Stress Technology Testing Testosterone Therapeutic Transfusion clinically significant erythroid differentiation ethnic diversity experimental study gene network genome wide association study improved individual patient innovation insight male men mouse genome p38 MAPK Signaling Pathway p38 Mitogen Activated Protein Kinase protein expression resilience response sex targeted treatment testosterone replacement therapy transfusion medicine

项目摘要

Project Summary Blood donors are a genetically diverse population with numerous biological variables including sex, race, and age that may affect red blood cell (RBC) storage and transfusion outcomes. We have demonstrated a sex dichotomy in RBC predisposition to hemolysis, for which male RBCs from humans or mice exhibit enhanced susceptibility to cold storage, osmotic shock, and oxidative stress. A key discovery of our studies is that orchiectomy or testosterone replacement therapy (TRT) in mice significantly modulates RBC predisposition to hemolysis in storage and after transfusion. This finding has alerted us to the potential risks associated with TRT in blood donors. Testosterone therapies have been recently identified as of one of the most overused medical practices in the US, and the lack of clear guidelines and risk assessment of RBC transfusion from TRT patients deem such donors eligible for donation, except for cases of suspected polycythemia. Our preliminary genome-wide association studies in 25 mouse strains suggested that sex differences in predisposition to hemolysis involve gene networks surrounding p38 MAPK, which may intensify hemolytic response during stress, and can be activated by testosterone. These observations inform our overarching hypothesis that testosterone modulates erythroid cell differentiation and biology leading to sex differences in RBC characteristics and kinase activity under hemolytic stress including cold storage. In the current proposal, we use innovative human and mouse studies to evaluate the impact of donor sex and testosterone on transfusion outcomes and to map out down-stream p38 MAPK signaling pathways that modulate RBC structure, function and integrity during storage and transfusion. In Aim 1, we will define the impact of TRT in blood donors on RBC storage and post transfusion recovery using a human to mouse transfusion model. In Aim 2, we will determine the molecular interactions between testosterone and p38 MAPK, and identify the p38 MAPK signaling hubs that impact RBC function and survival in storage. The impact of testosterone on p38 MAPK biology (Aim 2A) will be defined at different levels of erythroid cell differentiation using human erythroid cell lines; in mature RBCs from TRT patients before and 120 days after testosterone treatments; and in RBCs from mice expressing attenuated p38 MAPK activity (B6.Cg-Mapk14tm1.1Dvb/J). In all experiments, we will monitor for changes in protein expression downstream of p38 MAPK including MK2, HSP 27 and anion exchangr-1. Next, we will use mouse and donor (NHLBI RBC-Omics) genome-wide association (GWA) databases of sex differences in hemolysis to enhance discovery of signaling hubs associated with p38 MAPK and regulated by sex. Outcomes from this project are likely to advance the field of transfusion medicine by assessing the risks associated with transfusion of blood from TRT donors; providing new insights into the mechanisms that mediate sex differences in RBC storage stability; and identifying signaling hubs that can be targeted therapeutically to reduce the risk of hemolysis in transfusion practices.

项目摘要献血者是一个多样化的人群，具有许多生物学变量，包括性别，种族和可能影响红细胞（RBC）存储和输血结果的年龄。我们已经展示了性爱 RBC中的二分法对溶血的倾向对冷藏，渗透冲击和氧化应激的敏感性。我们研究的关键发现是小鼠中的鸡蛋切除术或睾丸激素替代疗法（TRT）显着调节RBC易感性在储存和输血后进行溶血。这一发现提醒我们与献血者中的trt。睾丸激素疗法最近被确定为最被过度使用的疗法美国的医疗实践以及缺乏明确的指南和对RBC输血的风险评估患者认为此类捐赠者有资格捐赠，但可疑的多余尚率除外。我们的初步全基因组菌株中的全基因组关联研究表明，性别差异溶血涉及围绕p38 MAPK的基因网络，这可能会加剧溶血反应压力，可以通过睾丸激素激活。这些观察结果为我们的总体假设提供了睾丸激素调节红系细胞分化和生物学，导致RBC的性别差异溶血应激下的特征和激酶活性，包括冷储存。在当前的提议中，我们使用创新的人和小鼠研究来评估供体性别和睾丸激素对输血的影响结果并绘制向下流p38 MAPK信号通路调节RBC结构，功能在存储和输血期间的完整性。在AIM 1中，我们将定义TRT对献血者对RBC的影响使用人类对小鼠输血模型的储存和后输血恢复。在AIM 2中，我们将确定睾丸激素和p38 MAPK之间的分子相互作用，并识别p38 MAPK信号枢纽这会影响RBC功能和存储中的生存。睾丸激素对P38 MAPK生物学的影响（AIM 2A）将使用人红细胞系在不同水平的红细胞细胞分化下定义；成熟睾丸激素治疗之前和120天后，来自TRT患者的RBC；在小鼠的RBC中表达衰减的P38 MAPK活动（B6.CG-MAPK14TM1.1DVB/J）。在所有实验中，我们将监视 p38 MAPK下游蛋白质表达的变化，包括MK2，HSP 27和阴离子Exchangr-1。下一个，我们将使用鼠标和供体（NHLBI RBC-omics）全基因组关联（GWA）性别数据库溶血的差异以增强与p38 MAPK相关的信号枢纽的发现并受到调节性别。该项目的结果可能通过评估风险来推动输血医学领域与从TRT供体中输血有关；提供有关机制的新见解调解RBC存储稳定性的性别差异；并识别可以针对的信号集线器治疗以降低输血实践中溶血的风险。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex-specific genetic modifiers identified susceptibility of cold stored red blood cells to osmotic hemolysis.

DOI：
10.1186/s12864-022-08461-4
发表时间：
2022-03-23
期刊：
BMC genomics
影响因子：
4.4
作者：
Fang F;Hazegh K;Mast AE;Triulzi DJ;Spencer BR;Gladwin MT;Busch MP;Kanias T;Page GP
通讯作者：
Page GP

Relationships between endogenous and exogenous testosterone and cardiovascular disease in men.

DOI：
10.1007/s11154-022-09752-7
发表时间：
2022-12
期刊：
REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
影响因子：
8.2
作者：
Thirumalai, Arthi;Anawalt, Bradley D.
通讯作者：
Anawalt, Bradley D.

Erythrocyte mitogen-activated protein kinases mediate hemolytic events under osmotic and oxidative stress and in hemolytic diseases.

DOI：
10.1016/j.cellsig.2022.110450
发表时间：
2022-11
期刊：
CELLULAR SIGNALLING
影响因子：
4.8
作者：
Hazegh, Kelsey;Fang, Fang;Kelly, Kathleen;Sinchar, Derek;Wang, Ling;Zuchelkowski, Benjamin E;Ufelle, Alexander C;Esparza, Orlando;Davizon-Castillo, Pavel;Page, Grier P;Kanias, Tamir
通讯作者：
Kanias, Tamir

Toxic masculinity in red blood cell units? Testosterone therapy in blood donors revisited.