Mechanisms of gene repression in erythroid cells

红系细胞基因抑制机制

• 批准号: nhmrc : 107232
• 负责人: Prof Merlin Crossley
• 金额: $ 15.58万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/mechanisms-gene-repression-erythroid-cells/96254
• 关键词: Mechanisms; gene; repression; erythroid; cells

Inherited disorders of the blood, such as sickle-cell anaemia and thalassaemia, result from mutations in the genes that produce haemoglobin. Current treatments can partially alleviate some of the debilitating symptoms of these diseases but these treatments have significant side effects, and despite the best efforts of clinicians, many patients succumb to their conditions at an early age. It has been observed that certain individuals exhibit a milder form of the disease, as a consequence of the reactivation of their foetal haemoglobin genes, (a distinct set of genes that would have been active in utero but are normally silenced around the time of birth). It is widely accepted that if pharmaceutical means can be found for reactivating the foetal haemoglobin genes then many patients would benefit. The regulation of the foetal globin genes, like most human genes, is complicated and there are few obvious means of increasing their activity. Nevertheless, it is believed that by investigating the molecular mechanisms by which they are controlled it will be possible to devise therapeutic agents that mimic these mechanisms or to develop agents that prevent the shutdown of the foetal genes around birth. To this end we have been working on the molecules that regulate the activity of the haemoglobin genes. We have recently cloned a number of DNA-binding proteins, and their co-factors, that appear to be involved in silencing foetal globin gene expression. This grant proposal is concerned with learning how these new molecules operate to silence gene expression as a first step towards designing agents that will prevent the silencing.

遗传性血液疾病，例如镰状细胞性贫血和地中海贫血，是由产生血红蛋白的基因突变引起的。目前的治疗方法可以部分缓解这些疾病的一些使人衰弱的症状，但这些治疗方法具有显着的副作用，尽管临床医生尽了最大努力，但许多患者在很小的时候就死于这些疾病。据观察，某些个体表现出较温和的疾病形式，这是由于其胎儿血红蛋白基因（一组在子宫内本来活跃但通常在出生时沉默的独特基因）重新激活的结果。 。人们普遍认为，如果能够找到重新激活胎儿血红蛋白基因的药物方法，那么许多患者将会受益。与大多数人类基因一样，胎儿珠蛋白基因的调节很复杂，并且几乎没有明显的方法来增加其活性。然而，人们相信，通过研究控制它们的分子机制，将有可能设计出模仿这些机制的治疗剂，或开发出防止出生前后胎儿基因关闭的药物。为此，我们一直致力于研究调节血红蛋白基因活性的分子。我们最近克隆了许多 DNA 结合蛋白及其辅助因子，它们似乎参与了胎儿珠蛋白基因表达的沉默。该拨款提案涉及了解这些新分子如何沉默基因表达，作为设计防止沉默的药物的第一步。