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.
项目总结
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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