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

• 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
• 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

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

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.

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: 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.

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: Transfusion
• 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: 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

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: Transfusion
• 影响因子: 2.9
• 作者: Hazegh K;Bravo MD;Kamel H;Dumont L;Kanias T
• 通讯作者: Kanias T