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:
- 金额:$ 38.52万
- 依托单位:
- 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:
- 关键词:AffectAgeAmericanAndrogensAnionsApoptosisAttenuatedBindingBiologicalBiological FactorsBiologyBlood BanksBlood CirculationBlood DonationsBlood TransfusionBlood donorCandidate Disease GeneCell Differentiation processCell LineCell SurvivalCell physiologyCellular StructuresCellular biologyCharacteristicsCodeCryopreservationDatabasesDiseaseErythrocyte TransfusionErythrocytesErythroid CellsErythropoiesisExhibitsGene ExpressionGenesGeneticGenetic DatabasesGenetic Predisposition to DiseaseGenomicsGoalsGuidelinesHemolysisHumanHuman GenomeKnock-outMAP Kinase GeneMapsMediatingMediator of activation proteinMedicalMembraneModelingMolecularMonitorMouse StrainsMusNational Heart, Lung, and Blood InstituteOrchiectomyOsmotic ShocksOutcomeOvariectomyOxidative StressPatientsPharmaceutical PreparationsPhosphotransferasesPolycythemiaPopulation HeterogeneityPopulation StudyPredispositionRaceRecoveryRiskRisk AssessmentSafetySex DifferencesSignal PathwaySignal TransductionStressTechnologyTestingTestosteroneTherapeuticTransfusionclinically significanterythroid differentiationethnic diversityexperimental studygene networkgenome wide association studyimprovedindividual patientinnovationinsightmalemenmouse genomep38 MAPK Signaling Pathwayp38 Mitogen Activated Protein Kinaseprotein expressionresilienceresponsesextargeted treatmenttestosterone replacement therapytransfusion 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
献血者是一个遗传多样性的人群,具有许多生物学变量,包括性别,种族,
可能影响红细胞(RBC)储存和输血结果的年龄。我们展示了一种性别
红细胞溶血倾向的二分法,其中来自人或小鼠的雄性红细胞表现出增强的溶血倾向。
对冷藏、渗透压休克和氧化应激的易感性。我们研究的一个关键发现是,
睾丸切除术或睾酮替代疗法(TRT)可显著调节小鼠红细胞倾向,
储存和输血后溶血。这一发现提醒我们,
献血者中的TRT。最近,替吉奥疗法被认为是最被滥用的疗法之一。
美国的医疗实践,以及缺乏明确的指导方针和TRT红细胞输注的风险评估
患者认为这些捐献者符合捐献条件,但疑似红细胞增多症的情况除外。我们的初步
对25种小鼠品系的全基因组关联研究表明,易感性存在性别差异
溶血涉及p38 MAPK周围基因网络,其可在溶血过程中增强溶血反应,
压力,并可由睾酮激活。这些观察为我们的总体假设提供了依据,
睾酮调节红系细胞分化和生物学,导致RBC中的性别差异
在溶血胁迫(包括冷藏)下的特性和激酶活性。在目前的提案中,我们
使用创新的人类和小鼠研究来评估供体性别和睾酮对输血的影响
结果,并绘制出下游p38 MAPK信号通路,调节RBC结构,功能,
以及在储存和输注过程中的完整性。在目标1中,我们将定义TRT在献血者中对RBC的影响。
储存和使用人-小鼠输注模型的输注后回收。在目标2中,我们将确定
睾酮和p38 MAPK之间的分子相互作用,并确定p38 MAPK信号传导枢纽
影响红细胞功能和储存存活率。睾酮对p38 MAPK生物学的影响(Aim 2A)
将使用人红系细胞系在不同水平的红系细胞分化下定义;在成熟红系细胞中,
睾酮治疗前和治疗后120天TRT患者的RBC;以及小鼠的RBC
表达减弱的p38 MAPK活性(B6. Cg-Mapk 14 tm 1.1Dvb/J)。在所有实验中,我们将监测
p38 MAPK下游蛋白表达的变化,包括MK2、HSP 27和阴离子交换剂r-1。接下来,
我们将使用小鼠和供体(NHLBI RBC组学)全基因组关联(GWA)性别数据库,
溶血的差异,以增强发现与p38 MAPK相关的信号中枢,并受
性该项目的结果可能会通过评估风险来推动输血医学领域的发展
与TRT献血者输血相关;提供了对TRT机制的新见解,
介导RBC储存稳定性的性别差异;并确定可以靶向的信号中枢
在治疗上减少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:
- 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.
男性内源性和外源睾丸激素与心血管疾病之间的关系。
- DOI:10.1007/s11154-022-09752-7
- 发表时间:2022-12
- 期刊:
- 影响因子:8.2
- 作者:Thirumalai, Arthi;Anawalt, Bradley D.
- 通讯作者:Anawalt, Bradley D.
Toxic masculinity in red blood cell units? Testosterone therapy in blood donors revisited.
- DOI:10.1111/trf.16658
- 发表时间:2021-11
- 期刊:
- 影响因子:2.9
- 作者:Hazegh K;Anawalt BD;Dumont LJ;Kanias T
- 通讯作者:Kanias T
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:
- 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
The prevalence and demographic determinants of blood donors receiving testosterone replacement therapy at a large USA blood service organization.
- DOI:10.1111/trf.15754
- 发表时间:2020-05
- 期刊:
- 影响因子:2.9
- 作者:Hazegh K;Bravo MD;Kamel H;Dumont L;Kanias T
- 通讯作者:Kanias T
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{{ truncateString('Tamir Kanias', 18)}}的其他基金
Effect of blood donor sex and inter-individual variability in plasma testosterone on the transfusion effectiveness and hemostatic potential of red blood cells and platelets
献血者性别和血浆睾酮个体间差异对红细胞和血小板输血有效性和止血潜力的影响
- 批准号:
10930183 - 财政年份:2018
- 资助金额:
$ 38.52万 - 项目类别:
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