The roles of retinoids and their receptors in haemopoiesis

造血干细胞（hematopoietic stem cells, hsc）是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）和其他血液疾病主要通过造血干细胞移植治疗。然而，由于其罕见发生，通常很难获得大量用于移植的造血干细胞，特别是从脐带血等造血干细胞来源。此外，需要操作造血干细胞的方案，如基因治疗，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缺乏成功。因此，在这种情况下，确定使我们能够在体外培养造血干细胞的培养条件是非常可取的。这一应用是基于CIA的研究，他们最近发现了维生素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。ATRA目前用于治疗急性早幼粒细胞白血病，因为它能促进白血病细胞的成熟。CIA已经证明ATRA对hsc有相反的作用，最近的数据强烈表明ATRA诱导hsc在体外扩张。本提案中概述的研究旨在进一步确定ATRA和其他维生素A衍生物（统称为类维生素A）在调节血细胞生成中的作用机制。第一个具体目标是确定类维生素a如何扩展造血干细胞。第二个具体目标将探讨不同的RARs在调节血细胞生成中的作用。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，对类维生素a在血细胞生成中的作用的深入了解也可能导致各种类型血液疾病的治疗方法的改进。

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.