Hsal 2, A Novel Homeobox Gene in Hematopoiesis

该提案的长期目标是确定Hsal 2在骨髓生成中的作用。HSAL 2是一个最近 鉴定了与果蝇中的Sal同源盒基因具有序列同源性的趋异同源盒基因。 Hsal家族成员突变导致多器官发育的Towns-Brockes综合征 缺陷Hsal 2表达存在于大多数人组织中，包括造血组织。几行 有证据表明Hsal 2可能参与了骨髓细胞的生成：（1）Hsal 2的转录调控是一个重要的机制， 由两个独立的启动子控制，并且两个启动子都具有多个推定的结合位点， 对骨髓生成至关重要的调控基因，包括Wilms肿瘤抑制基因（WT 1）和视黄酸 （2）WT 1抑制Hsal 2启动子活性，而维甲酸（RA）激活Hsal 2启动子活性 （3）Hsal 2表达与髓系细胞一致 （4）Hsal 2缺失小鼠中的骨髓群体显著减少。因此，我假设 细胞内WT 1/RAR-α/Hsal 2通路可能在正常造血中起作用。生物 Hsal 2在骨髓生成中的功能将通过Hsal 2同种型在造血干细胞中的过表达来研究 细胞、骨髓细胞系和四环素诱导的胚胎干细胞的体外研究，以及 体内Hsal 2缺失小鼠。我们将继续研究Hsal 2的转录调控， WT_1与RAR_m结合位点的鉴定WT_1与RAR_t的拮抗作用 将通过在骨髓细胞系中过表达WT 1来进一步探索对Hsal 2表达的影响。知识 通过这些研究获得的信息将有助于更好地理解正常造血的关键途径。 并帮助开发新的策略来对抗白血病。首席研究员Li Chai博士将进行 实验室研究的指导下，赞助商，博士黛安克劳斯，和一个咨询委员会。在 此外，这项建议的另一个目的是作为一种工具，将候选人培养成 造血和白血病领域的独立和富有成效的研究者。

The long-term goal of this proposal is to define the role of Hsal2 in myelopoiesis. Hsal2 is a recently identified divergent homeobox gene that has sequence homology to the Sal homeobox gene in Drosophila. Mutations of Hsal family member lead to Townes-Brockes syndrome with multiple organ developmental defects. Hsal2 expression is present in most human tissues including hematopoietic tissues. Several lines of evidence suggest that Hsal2 may be involved in myelopoiesis: (1) The transcriptional regulation of Hsal2 is controlled by two independent promoters and both promoters bear multiple putative binding sites for regulatory genes critical for myelopoiesis, including Wilms' tumor suppression gene (WT 1) and retinoic acid receptor-c_ (RAR); (2) WT 1 represses both Hsal2 promoter activities while retinoic acid (RA) activates Hsal2 expression in a luciferase reporter gene system; (3) Hsal2 expression coincides with the myeloid lineage commitment; (4) The myeloid population in Hsal2-null mice is significant reduced. Therefore, I hypothesize that an intracellular WT 1/RAR-a/Hsal2 pathway may play a role in normal hematopoiesis. The biological function of Hsal2 in myelopoiesis will be studied by overexpression of Hsal2 isoforms in hematopoietic stem cells, myeloid cell lines, and tetracycline-inducible embryonic stem cells in vitro, and characterization of Hsal2-null mice in vivo. We will continue to characterize the transcriptional regulation of Hsal2 with a focus on identification of the binding sites of WT1 and RAR-m The antagonistic effect between WT1 and RAR-_t on Hsal2 expression will be further explored by overexpression of WT1 in myeloid cell lines. The knowledge gained by these studies will contribute to better understanding of pathways critical for normal hematopoiesis and help to develop novel strategies to combat leukemia. The principal investigator, Dr. Li Chai will conduct the laboratory research under the guidance of a sponsor, Dr. Diane Krause, and an advisory committee. In addition, a further objective of this proposal is to serve as a vehicle for the development of the candidate into an independent and productive investigator in the area of hematopoiesis and leukemogenesis.