SickleGenAfrica:Sickle Cell Disease Genomics Network of Africa

SickleGenAfrica：非洲镰状细胞病基因组学网络

• 批准号: 10240492
• 负责人: Gordon Akanzuwine Awandare
• 金额: $ 108.81万
• 依托单位: UNIVERSITY OF GHANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240492
• 关键词: Acute; Address; Adolescent; Adult; Affect; Africa; Africa South of the Sahara; African; Award; Bacteria; Bacterial Infections; Bioinformatics; Birth; Cameroon; Cardiopulmonary; Cardiovascular system; Cause of Death; Cessation of life; Child; Chronic; Collaborations; Country; Death Rate; Disease; Drops; Ensure; Fostering; Functional disorder; Future; Genetic; Genetic Diseases; Genetic Markers; Genetic Research; Genetic Variation; Genetic study; Genomics; Ghana; Goals; Hematological Disease; Heme; Hemoglobin; Hemolysis; Hemolytic Anemia; Hemopexin; Hospitalization; Infant; Inflammation; Inflammatory; Injury; Institution; International; Knowledge; Link; Malaria; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal Screening; Nigeria; North America; Organ; Organ failure; Outcome; Parasitemia; Patients; Pattern; Penicillins; Phenotype; Population; Prevention; Prophylactic treatment; Proteins; Research; Research Personnel; Research Project Grants; Risk Factors; Science; Scientist; Sickle Cell; Sickle Cell Anemia; Sudden Death; Tanzania; Testing; Tissues; Training; Transgenic Organisms; Universities; Variant; Vascular Diseases; biobank; body system; career; clinical phenotype; cohort; extracellular; genome-wide; genomic data; heme oxygenase-1; improved; infection management; molecular hematology; mortality; neonate; organ growth; prevent; prophylactic; sickling; synergism; tissue injury; validation studies

Sickle cell disease (SCD) is the commonest genetic disorder in the World. It is most prevalent in Africa. We have established SickleGenAfrica:Sickle Cell Disease Genomics Network of Africa to build capacity locally to enable African scientists study genomics of SCD on the continent. The network consists of a core of investigators in nine institutions in four sub-Saharan African (SSA) countries (Cameroon, Ghana, Nigeria and Tanzania). Our prior studies showed that 1.8% of births in Ghana are affected by SCD. Penicillin prophylaxis in neonates has reduced mortality in SCD, however, this progress has not been matched by advancements in reducing deaths due to other causes. End-stage organ damage is now the leading cause of death among SCD patients in the West and it is poised to become the major cause of death in Africa once prevention and prompt management of infections becomes widely implemented on the continent. Inflammatory molecules such as free heme released from hemolysis cause severe tissue injury that ultimately causes organ damage in SCD. Malaria causes severe intravascular hemolysis and potentially exacerbates hemolysis-related tissue damage in SCD uniquely in Africa. There is a hierarchy of cytoprotective proteins that neutralize the inflammatory molecules released by hemolysis. Studies in transgenic SCD mice indicate some of these cytoprotective proteins such as hemopexin and heme oxygenase-1, influence cardiopulmonary and vascular dysfunctions in SCD. Although these findings have not been validated in patients, we have discovered wide variations in the level of several key hemolysis cytoprotective proteins among patients, suggesting that these proteins modify the clinical phenotype of SCD perhaps most strongly in Africa. Hitherto, the genetics of this variation has not been defined. In addition, the functional murine studies are limited to a few organ systems, and to scientists in the West, since transgenic sickle mice colonies are not available in institutions in Africa. We seek to address these gaps by accomplishing seven objectives: (1) Phenotype 7, 000 SCD patients and controls in four SSA countries; (2) perform three collaborative genetic research project each with a functional validation study in transgenic sickle mice; (3) Establish a molecular hematology and sickle cell mouse core in Ghana; (4) Leverage an existing H3Africa biorepository to establish a SCD biorepository core in Nigeria; (5) Establish a bioinformatics core at the University of Pittsburgh to analyze the genomics data obtained by the H3Africa Center and to provide expertise to upgrade bioinformatics nodes in Ghana in partnership with H3ABionet; (6) Implement a career pipeline model to train future science leaders in Africa in blood disorders research; (7) establish a cross cutting Administrative core enabling synergy and coordination of network activities with a robust sustainability plan for the H3Africa Center. The University of Ghana is submitting this application with strong institutional support from the University of Pittsburgh.

镰状细胞病（SCD）是世界上最常见的遗传性疾病。它在非洲最为流行。我们 建立了非洲镰状细胞病基因组学网络，在当地建立能力， 使非洲科学家能够在非洲大陆研究SCD的基因组学。该网络包括一个核心， 撒哈拉以南非洲四个国家（喀麦隆、加纳、尼日利亚和 坦桑尼亚）。我们之前的研究表明，加纳1.8%的新生儿受到SCD的影响。青霉素预防 新生儿SCD死亡率降低，然而，这一进展并没有与 减少其他原因造成的死亡。终末期器官损伤现在是SCD死亡的主要原因 一旦预防和及时治疗， 感染管理在非洲大陆得到广泛实施。炎症分子，如游离 溶血释放血红素导致严重的组织损伤，最终导致SCD中的器官损伤。 疟疾引起严重的血管内溶血，并可能加剧溶血相关的组织损伤， SCD在非洲独一无二。有一个层次的细胞保护蛋白， 溶血释放的分子。在转基因SCD小鼠中的研究表明，其中一些细胞保护作用 血红素结合蛋白和血红素氧合酶-1等蛋白质影响心肺和血管功能障碍， SCD。尽管这些发现尚未在患者中得到验证，但我们发现， 患者中几种关键的溶血细胞保护蛋白的水平，表明这些蛋白质修饰 SCD的临床表型可能在非洲最强。然而，这种变异的遗传学并没有 被定义。此外，功能性小鼠研究仅限于少数器官系统， 在西方，由于非洲的机构没有转基因镰状小鼠群体。我们寻求解决 通过完成以下七个目标来弥补这些差距：（1）在四个SSA中的表型7，000名SCD患者和对照 国家;（2）执行三个合作遗传研究项目，每个项目都有一项功能验证研究， 转基因镰状小鼠;（3）在加纳建立分子血液学和镰状细胞小鼠核心;（4） 利用现有的H3非洲生物储存库在尼日利亚建立SCD生物储存库核心;（5）建立 匹兹堡大学的生物信息学核心，分析H3 Africa获得的基因组学数据。 中心，并与H3 ABionet合作，为更新加纳的生物信息学节点提供专门知识;（6） 实施职业管道模式，在非洲培养血液病研究方面的未来科学领导人;（7） 建立一个跨部门的行政核心，使网络活动能够与 为H3非洲中心制定强有力的可持续发展计划。加纳大学正在提交此申请， 来自匹兹堡大学的强大机构支持。

项目成果

Sickle cell disease as a vascular disorder.

镰状细胞病是一种血管疾病。

• DOI: 10.1080/17474086.2020.1758555
• 发表时间: 2020
• 期刊: Expert review of hematology
• 影响因子: 2.8
• 作者: Ofori-Acquah,SolomonF

Cardiac expression of HMOX1 and PGF in sickle cell mice and haem-treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2).

• DOI: 10.1111/bjh.16129
• 发表时间: 2019-12
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Gbotosho OT;Ghosh S;Kapetanaki MG;Lin Y;Weidert F;Bullock GC;Ofori-Acquah SF;Kato GJ
• 通讯作者: Kato GJ

Sickle Cell Disease Genomics of Africa (SickleGenAfrica) Network: ethical framework and initial qualitative findings from community engagement in Ghana, Nigeria and Tanzania.

• DOI: 10.1136/bmjopen-2020-048208
• 发表时间: 2021-07-23
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Anie KA;Olayemi E;Paintsil V;Owusu-Dabo E;Adeyemo TA;Sani MU;Galadanci NA;Nnodu O;Tluway F;Adjei DN;Mensah P;Sarfo-Antwi J;Nwokobia H;Gambo A;Benjamin A;Salim A;Osae-Larbi JA;Ofori-Acquah SF;SickleGenAfrica Network
• 通讯作者: SickleGenAfrica Network

Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.

游离血红素通过 NRF2 抗氧化反应信号调节胎盘生长因子。

• DOI: 10.1016/j.freeradbiomed.2019.08.009
• 发表时间: 2019
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Kapetanaki,MariaG;Gbotosho,OluwabukolaT;Sharma,Deva;Weidert,Frances;Ofori-Acquah,SolomonF;Kato,GregoryJ
• 通讯作者: Kato,GregoryJ