RA RECEPTOR REGULATION ON HEMATOPOIETIC STEM CELLS

RA 受体对造血干细胞的调节

• 批准号: 6358968
• 负责人: STEVEN Collins COLLINS
• 金额: $ 20.94万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6358968
• 关键词: Retroviridae; bone marrow; cell differentiation; gene expression; growth factor; growth media; hematopoiesis; hematopoietic stem cells; laboratory mouse; nuclear receptors; receptor expression; retinoate; retinoid binding proteins; tissue /cell culture; transfection /expression vector

All-trans retinoic acid (ATRA) triggers the differentiation of malignant pro-myelocytes and is now part of the standard remission induction/maintenance regimen for patients presenting with acute promyelocytic leukemia (APL). However, the effects of ATRA on other hematopoietic precursors is not as well characterized. We have recently accumulated evidence indicating that activated retinoic acid receptors enhance the generation and/or maintenance of relatively early multi- potent hematopoietic precursors including radioprotective cells, CFU-S, and short and long-term marrow repopulating stem cells. These observations suggest an unexpected and seemingly paradoxical dual role for retinoic acid receptors in regulating hematopoiesis, with one role being to enhance the commitment and terminal differentiation of relatively late hematopoietic progenitors but a second role being to stimulate the proliferation and perhaps self-renewal of primitive hematopoietic precursors/stem cells. It is this dual role of retinoic acid receptors that we wish to explore in the present application. The Specific Aim I studies will attempt to identify the in vitro culture conditions that optimize the ATRA effects on the generation/maintenance of hematopoietic stem cells in liquid suspension cultures. Specific Aim II will involve directly determining whether ATRA enhances the self- renewal of hematopoietic stem cells both in vitro and in vivo. Specific Aim III will address the question of whether ATRA enhances the efficiency of transducing hematopoietic stem cells with retroviral vectors. In Specific Aim IV we will attempt to identify the target genes that may be regulated by ATRA in primitive hematopoietic precursor with particular emphasis on Hox gene expression. These studies will provide insight into the roles of RA receptors in regulating primitive hematopoietic precursors and may also have direct clinical application to the ex vivo expansion and gene therapy of hematopoietic stem cells.

全反式视黄酸（ATRA）触发恶性促肌细胞的分化，现在是患有急性前临床前白血病（APL）患者的标准缓解诱导/维持方案的一部分。但是，ATRA对其他造血前体的影响并没有很好地表征。我们最近积累了证据，表明活化的视黄酸受体可以增强相对早期多重有效的造血前体的产生和/或维持，包括辐射保护细胞，CFU-S，以及短期和长期的骨髓重现干细胞。这些观察结果表明，视黄酸受体在调节造血中具有出乎意料且看似矛盾的双重作用，其中一种作用是增强相对较晚的造血祖细胞的承诺和终端分化，但第二个作用是刺激促进型血脂前胞细胞的增殖和自我重生的第二个作用。我们希望在本应用中探索视黄酸受体的双重作用。具体目的I研究将尝试确定体外培养条件，以优化ATRA对液体悬浮培养物中造血干细胞的产生/维持的影响。特定的目标II将直接确定ATRA是否会在体外和体内增强造血干细胞的自我更新。特定的目标III将解决ATRA是否增强用逆转录病毒载体转导造血干细胞的效率的问题。在特定目标IV中，我们将尝试鉴定原始造血前体中ATRA可能调节的靶基因，并特别强调HOX基因表达。这些研究将洞悉RA受体在调节原始造血前体中的作用，并可能直接临床应用于造血干细胞的离体扩张和基因治疗。