Characterization of novel Ikaros related proteins

新型 Ikaros 相关蛋白的表征

• 批准号: nhmrc : 211000
• 负责人: Prof Merlin Crossley
• 金额: $ 28.16万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/characterization-novel-ikaros-related-proteins/97897
• 关键词: Characterization; novel; Ikaros; related; proteins

DNA-binding proteins regulate gene expression and co-ordinate normal patterns of development. We are investigating a set of DNA-binding proteins, termed the Ikaros family. These proteins are known to be important regulators of white blood cell production and mutations that interfere with Ikaros activity are associated with aggressive childhood leukaemias that are resistant to treatment. Recently, it has become apparent that Ikaros proteins also regulate genes in red blood cells. One observation is that Ikaros plays a role in silencing the foetal haemoglobin genes. The haemoglobin genes have been extensively studied because diseases, such as beta-thalassaemia, which are caused by mutations in the adult haemoglobin genes, are among the most common genetic diseases known. One strategy to alleviate beta-thalassaemia centres around re-activating the foetal globin genes and thereby re-supplying globin to adults who have only mutant forms. In this context, the observation that Ikaros plays a role in foetal globin silencing is of considerable medical significance. We have recently identified two new regulatory proteins that are related to Ikaros and are found in red blood cells. Little is known about these proteins but they can directly bind to Ikaros and they are capable of silencing gene expression. We therefore wish to test the hypothesis that they work together with Ikaros to silence gene expression. Ultimately we expect that understanding how these proteins and Ikaros operate will suggest new strategies for re-activating the silent foetal globin genes to treat beta-thalassaemia, as well as preventing the proliferation of white blood cells carrying mutant Ikaros proteins.

DNA 结合蛋白调节基因表达并协调正常的发育模式。我们正在研究一组 DNA 结合蛋白，称为 Ikaros 家族。已知这些蛋白质是白细胞生成的重要调节因子，干扰 Ikaros 活性的突变与对治疗产生耐药性的侵袭性儿童白血病有关。最近，人们发现 Ikaros 蛋白还调节红细胞中的基因。一项观察结果表明，Ikaros 在沉默胎儿血红蛋白基因方面发挥着作用。血红蛋白基因已被广泛研究，因为诸如β-地中海贫血等由成人血红蛋白基因突变引起的疾病是已知的最常见的遗传疾病之一。缓解β地中海贫血的一种策略是重新激活胎儿珠蛋白基因，从而为仅具有突变形式的成年人重新提供珠蛋白。在这种背景下，观察到Ikaros在胎儿珠蛋白沉默中发挥作用具有相当大的医学意义。我们最近发现了两种与 Ikaros 相关且存在于红细胞中的新调节蛋白。人们对这些蛋白质知之甚少，但它们可以直接与 Ikaros 结合，并且能够沉默基因表达。因此，我们希望检验它们与 Ikaros 一起沉默基因表达的假设。最终，我们期望了解这些蛋白质和 Ikaros 的运作方式将提出重新激活沉默的胎儿珠蛋白基因以治疗 β 地中海贫血以及防止携带突变 Ikaros 蛋白质的白细胞增殖的新策略。