The role of HbF decline and its determinants on Sickle Cell Disease expression in the first three years of life.

项目摘要 背景：坦桑尼亚已将SCD作为一种重要的公共卫生状况纳入其国家卫生政策。 国家非传染性疾病（NCD）战略。坦桑尼亚排名第五，仅次于尼日利亚、刚果民主共和国、 印度和安哥拉是SCD出生人数最多的国家。最近的估计显示 坦桑尼亚每年有超过10，000名5岁以下的SCD儿童死亡， 占U 5死亡总数的6.6%。发育调节的生理和病理变化 发生在儿童早期，可能影响SCD的自然史。As血红蛋白γ→β 珠蛋白基因转换发生;镰状血红蛋白（HbS）逐渐取代胎儿血红蛋白 （HbF）。疾病表现，包括溶血、疼痛发作、贫血，开始于 这一时期，并贯穿一生。血红蛋白转换和HbF下降在 在SCD疾病表达中的中心作用。HbF下降的决定因素， HbF下降的变化以及这些变化与前三年疾病表达的关系 生活是不明确的。具体目标：（1）.确定HbF下降与SCD的相关性 在生命的前三年的临床表现（2）。以确定与之相关的遗传因素 有和没有SCD的婴儿的HbF下降（3）。为了研究模式的变化， 患有和不患有SCD的婴儿的HbF下降率。研究的意义和相关性 HbF研究的最终目标是开发干预措施。 了解HbF下降在生命早期SCD疾病表达中的作用将有助于了解 HbF干预的时间点。此外，阐明HbF的遗传决定因素， 下降将突出HbF转换/合成的机制，因此 干预诱导成年期HbF合成。的特色和创新， 项目：这项研究将在坦桑尼亚建立第一个SCD出生队列。拟定研究 将对400名患有和没有SCD的婴儿进行为期三年的随访，以研究SCD的表达， HbF下降。方法：我们将使用现有的新生儿筛查和免疫接种 平台，以登记和跟踪婴儿从出生到三年。基因表达谱将 用于询问与HbF下降相关的基因，同时靶向下一代 测序将研究已知的HbF编码和非编码变体。我们将调查 遗传因素是否影响HbF下降的变异谱和临床 表情预期结果：迄今为止，只有一种可用的SCD药物，即羟基脲， 导致HbF水平升高。这项研究的结果将增加对 有机会开发额外的干预措施以及更好地管理羟基脲。

PROJECT SUMMARY Background: Tanzania has included SCD as an important public health condition in the country’s non communicable diseases (NCD) strategy. Tanzania ranks 5th, after Nigeria, DRC, India and Angola in countries with the highest numbers of SCD births. Recent estimates show that over 10,000 SCD children under 5 years of age (U5) die annually in Tanzania, representing 6.6% of overall U5 deaths. Developmentally-regulated physiological and pathological changes occur in early childhood that may impact on the natural history of SCD. As hemoglobin γ→β globin gene switching occurs; sickle haemoglobin (HbS) gradually replaces fetal haemoglobin (HbF). Disease manifestations, including haemolysis, painful episodes, anaemia, start during this period and continues throughout life. Haemaglobin switching and HbF decline plays a central role in SCD disease expression. The determinants of HbF decline, the spectrum of variation of HbF decline and how these relate to disease expression in the first three years of life is not clear. Specific Aims: (1). To determine the association of HbF decline with SCD clinical expression in the first three years of life (2). To determine the genetic factors associated with HbF decline in babies with and without SCD (3). To study the variation of the pattern and rate of HbF decline in babies with and without SCD. Significance of the study and relevance to public health: The ultimate goal of HbF research is the development of interventions. Understanding the role of HbF decline in SCD disease expression in the early life will inform on the time point for HbF interventions. In addition, elucidating the genetic determinants of HbF decline will highlight the mechanism of HbF switching/ synthesis and hence development of interventions to induce HbF synthesis in adulthood. The unique features and innovation of the project: This study will establish the first SCD birth cohort in Tanzania. The proposed study will follow 400 babies with and without SCD for three years to investigate SCD expression and HbF decline. The methodology: We will use existing newborn screening and immunization platforms to enroll and follow babies from birth up to three years. Gene expression profiling will be used to interrogate genes associated with HbF decline while targeted next generation sequencing will investigate known HbF coding and non coding variants. We will investigate whether genetic factors influence the spectrum of variation of HbF decline and clinical expression. Expected results: To date, there is only one available SCD drug, hydroxyurea, that results in increased HbF levels. Findings from this study will increase knowledge on the opportunities to develop additional interventions as well as better administration of hydroxyurea.