Functional characterisation of regulators of human globin gene switching

红细胞产生血红蛋白，这是一个由两个α-珠蛋白链和两个β-珠蛋白链组成的四聚体。血红蛋白与氧气可逆地相互作用，有效地在肺部和身体其他部位之间运送氧气。血红蛋白分子及其携带的红细胞的完整性对所有有血液的生物体的生命都是至关重要的。构成血红蛋白的α-珠蛋白链和β-珠蛋白链是由骨髓中的红细胞前体根据遗传基因蓝图(基因)产生的。由β-珠蛋白基因缺陷引起的遗传性疾病是人类最常见的遗传性疾病。不能产生β-珠蛋白的儿童患有一种称为β-地中海贫血症的疾病。它们从6个月大开始就依赖输血，需要进行强化的螯合治疗(输液)，以避免严重的铁超载。在西方文化中，人们的平均预期寿命约为30岁。没有治愈的方法。在无法获得可靠血液供应的第三世界国家，死亡发生得更早。患者在感染血液传播病毒后，如乙肝、丙型肝炎和艾滋病病毒，艾滋病毒。镰状细胞性贫血也是一种非常常见的疾病。这是由于β-珠蛋白基因中的一个DNA碱基突变导致了正常数量的有缺陷的β-珠蛋白分子(HBS)的产生。在低氧条件下，HBS分子在红细胞内聚合，并对其造成不可逆转的损害。这些红细胞在整个循环中被困在细小的毛细血管中，导致小的梗塞，从而导致严重的疼痛和器官损伤。第三世界的预期寿命为2岁，西方为20-30岁。这两种疾病的讽刺之处在于，有一种完全正常的胎儿珠蛋白基因在胎儿时期一直处于沉默状态。这项资助旨在了解从胎儿到成人珠蛋白基因使用的转换机制，以便在患有b地中海贫血和镰状细胞疾病的成年人中逆转这种转换。

Red blood cells produce haemoglobin, a tetramer of two alpha globin chains and two beta-globin chains. Haemoglobin reversibly interacts with oxygen in such a way that it efficiently shuttles oxygen between the lungs and the rest of the body. Integrity of the hemoglobin molecule, and red cells which carry it, is essential for life of all organisms with blood. The alpha-globin and beta-globin chains that make up haemoglobin are prodcued by red cell precursors in the bone marrow according to the genetic blueprint (genes) that are inherited. Genetic disorders resulting from defects in the beta-globin gene are the most common inherited disorders of man. Children who fail to make beta-globin have a disease known as beta-thalassaemia. They are transfusion dependent from ~ 6 months of age and need intensive chelation therapy (infusions) to avoid the serious consequnces of iron overload. The average life expectancy in Western cultures is ~ 30 years. There is no cure. In third world countries where a reliable blood supply is unavailable, death occurs earlier. Patients are aften infected with blood born viruses such as hepatitis B, hepatitis C and the AIDS virus, HIV. Sickle cell anaemia is also a very common disease. It is due to a single DNA base mutation at in the beta-globin gene that results in production of normal amounts of a defective beta-globin molecule (HbS). In low oxygen, HbS molecules polymerize in red cells and irreversibly damage them. These red cells get trapped in small blood capillaries throughout the circulation causing small infarcts which results in severe pain and organ damage. The life expectancy is <2 years in the thrid world and ~20-30 years in the west. The irony of these two diseases is that there is a perfectly normal fetal globin gene that has been silenced during fetal life. This grant aims to understand the mechanism of the switch from fetal to adult globin gene usage so it can be reversed in adults with b-thalassemia and sickle cell disease