SickleGenAfrica:Sickle Cell Disease Genomics Network of Africa

镰状细胞病(SCD)是世界上最常见的遗传病。它在非洲最为流行。我们 已经建立了SickleGenAfrica：非洲镰状细胞疾病基因组学网络，以在当地建设能力 使非洲科学家能够研究非洲大陆上的SCD基因组学。该网络由以下核心组成 四个撒哈拉以南非洲(SSA)国家(喀麦隆、加纳、尼日利亚和#年)的九个机构的调查员 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。青霉素在中国的预防 新生儿降低了SCD的死亡率，然而，这一进展并没有与以下方面的进展相匹配 减少因其他原因造成的死亡。终末期器官损伤现在是SCD的主要死亡原因 西方患者一旦预防和及时死亡，势必成为非洲的主要死因 感染管理在非洲大陆得到广泛实施。炎症分子如游离 溶血释放的血红素会造成严重的组织损伤，最终导致SCD的器官损伤。 疟疾导致严重的血管内溶血，并有可能加剧与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，其中一些具有细胞保护作用 血凝素和血红素氧合酶-1等蛋白质对心肺和血管功能障碍的影响 SCD。尽管这些发现尚未在患者身上得到证实，但我们发现，在 几种关键的溶血细胞保护蛋白在患者中的水平，提示这些蛋白可以改变 SCD的临床表型可能在非洲最强烈。到目前为止，这种变异的遗传学还没有 已经被定义了。此外，对小鼠功能的研究仅限于几个器官系统，而科学家在 在西方，因为非洲的机构中没有转基因镰刀鼠群体。我们寻求解决 这些差距通过完成七个目标：(1)表型7000名SCD患者和四个SSA的对照 国家；(2)执行三个合作遗传研究项目，每个项目都在#年进行功能验证研究 转基因镰刀鼠；(3)在加纳建立分子血液学和镰刀鼠核心；(4) 利用现有的H3非洲生物库在尼日利亚建立SCD生物库核心；(5)建立 匹兹堡大学生物信息学核心，分析H3非洲获得的基因组数据 与H3ABionet合作，提供专业知识，以升级加纳的生物信息学节点；(6) 实施职业管道模式，培训非洲未来的血液疾病研究科学带头人；(7) 建立一个贯穿各领域的行政核心，使网络活动能够与 H3非洲中心的稳健可持续发展计划。加纳大学提交了这份申请书 来自匹兹堡大学的强有力的机构支持。

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.