SickleGenAfrica:Sickle Cell Disease Genomics Network of Africa

SickleGenAfrica：非洲镰状细胞病基因组学网络

基本信息

批准号：
10000986
负责人：
Gordon Akanzuwine Awandare
金额：
$ 109.44万
依托单位：
UNIVERSITY OF GHANA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000986
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

项目摘要

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。我们已建立 SickleGenAfrica：非洲镰状细胞病基因组学网络，以建设当地能力，以使非洲科学家能够研究该大陆的 SCD 基因组学。该网络由一个核心组成四个撒哈拉以南非洲国家（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。青霉素预防新生儿的 SCD 死亡率有所降低，然而，这一进展并未与以下方面的进展相匹配：减少其他原因造成的死亡。终末期器官损伤现已成为 SCD 死亡的主要原因一旦预防和及时预防，它将成为非洲主要死亡原因非洲大陆广泛实施感染管理。炎症分子，如游离溶血释放的血红素会导致严重的组织损伤，最终导致 SCD 的器官损伤。疟疾会导致严重的血管内溶血，并可能加剧溶血相关的组织损伤 SCD在非洲独一无二。有一系列细胞保护蛋白可以中和炎症溶血释放的分子。对转基因 SCD 小鼠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加氧酶-1等蛋白质会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，患者中几种关键溶血细胞保护蛋白的水平，表明这些蛋白修饰 SCD 的临床表型可能在非洲最为强烈。迄今为止，这种变异的遗传学尚未被证实。被定义。此外，功能性小鼠研究仅限于少数器官系统，并且仅限于科学家西方国家，因为非洲的机构中没有转基因镰状小鼠群体。我们寻求解决通过实现七个目标来弥补这些差距：(1) 四个 SSA 中的表型 7、000 名 SCD 患者和对照国家； (2) 开展三个合作遗传研究项目，每个项目都进行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 H3Africa 生物样本库在尼日利亚建立 SCD 生物样本库核心；（五）建立匹兹堡大学生物信息学核心分析 H3Africa 获得的基因组数据中心并与 H3ABionet 合作提供专业知识以升级加纳的生物信息学节点； (6) 实施职业管道模型，培训非洲血液疾病研究方面的未来科学领袖； (7) 建立一个跨领域的管理核心，以实现网络活动的协同和协调 H3Africa 中心稳健的可持续发展计划。加纳大学正在提交此申请匹兹堡大学的强大机构支持。