The roles of retinoids and their receptors in haemopoiesis

类维生素A及其受体在造血中的作用

• 批准号: nhmrc : 251531
• 负责人: A/Pr Louise Purton
• 金额: $ 31.66万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/roles-retinoids-receptors-haemopoiesis/95926
• 关键词: roles; retinoids; their; receptors; haemopoiesis

Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, such as gene therapy, have been largely unsuccessful, in part due to the lack of success in growing HSCs outside of the body. In such situations, therefore, determining culture conditions that would enable us to grow HSCs outside of the body are highly desirable. This application is based on the studies of CIA, who recently made the novel discoveries that the vitamin A derivative, all-trans retinoic acid (ATRA) has different effects in the regulation of blood cell production. ATRA is currently used in the treatment of acute promyelocytic leukaemia, as it enhances the maturation of the leukaemic cells. CIA has demonstrated that ATRA has the opposite effect on HSCs, with recent data strongly suggesting that ATRA induces the expansion of HSCs outside of the body. The studies outlined in this proposal seek to further define the mechanisms involved in these effects of ATRA and other vitamin A derivatives (collectively termed retinoids) in the regulation of blood cell production. The first specific aim will determine how retinoids expand HSCs. The second specific aim will explore the roles of the different RARs in the regulation of blood cell production. These studies have direct clinical relevance in improving protocols for transplantation and gene therapy of HSCs. Furthermore, insight gained into the roles of retinoids in blood cell production may also lead to the improvement of treatments of various types of blood disorders.

造血干细胞(HSCs)是目前研究最广泛的成体干细胞。造血干细胞具有巨大的潜力，可以在人的一生中维持血细胞的产生。癌症(白血病)和其他血液疾病很大程度上是通过移植造血干细胞来治疗的。然而，由于它们的罕见发生，往往很难获得大量的HSCs用于移植，特别是从脐带血等HSCs来源。此外，需要操纵造血干细胞的方案，如基因疗法，在很大程度上是不成功的，部分原因是在体外培养造血干细胞方面缺乏成功。因此，在这种情况下，确定能够使我们在体外培养HSCs的培养条件是非常可取的。这一应用是基于CIA的研究，他最近新发现维生素A衍生物全反式维甲酸(ATRA)在调节血细胞生成方面具有不同的作用。全反式维甲酸目前用于治疗急性早幼粒细胞白血病，因为它促进了白血病细胞的成熟。CIA已经证明ATRA对HSCs有相反的作用，最近的数据强烈表明ATRA诱导HSCs在体外扩张。这项建议中概述的研究试图进一步确定ATRA和其他维生素A衍生物(统称为维甲酸)在调节血细胞生成方面的这些作用所涉及的机制。第一个具体目标将决定维甲酸是如何扩张HSC的。第二个具体目标将探索不同的RARs在调节血细胞生产中的作用。这些研究对改进造血干细胞移植和基因治疗方案具有直接的临床意义。此外，对维甲酸在血细胞生成中的作用的深入了解也可能导致各种血液疾病的治疗方法的改进。