Characterization of HoxBS, a key regulator in blood vessel formation

血管形成在健康和疾病中是必不可少的。内皮细胞的形成和血管生成反应的调控机制目前还不清楚，我们已经确定转录因子HoxB 5通过其对flk-1增强子的调节作用而成为内皮细胞发育的重要调控因子。我们的初步数据表明，HoxB 5在血管成熟中也起着关键作用。在这个项目中，我们将：1）通过体外和体内的血管功能获得和丧失模型，详细研究HoxB 5在血管形成中的作用。2)阐明HoxB 5调节血管生成素-2的分子机制--这是我们在初步实验中发现的一种作用，从而提出了这一建议。血管生成素-2与内皮细胞的不稳定有关，而内皮细胞的不稳定是血管生成出芽的先决条件。因此，HoxBS可能控制血管生成中的两个关键步骤-内皮细胞去稳定和激活。3)使用体外和体外模型将HoxBS定位在已知的血管生成和血管生成信号级联中。我们将特别关注microRNA对HoxBS的调控，因为计算机模拟预测表明，参与血管形成的microRNA在HoxBS基因中具有潜在的结合位点。迄今为止获得的数据表明，HoxBS在血管生成信号中的高层次位置与HoxBS在血管形成中的关键作用一致。

Blood vessel formation is essential in health and disease. The regulatory mechanisms thatcontrol the formation and angiogenic response of endothelial cells are far from understood.We have identified the transcription factor HoxB5 as an important regulator of endothelialcell development by its regulatory role on the flk-1 enhancer. Our preliminary data presentedhere indicate that HoxB5 plays also a key role in blood vessel maturation. In this project wewill: 1) investigate the role of HoxB5 on blood vessel formation in detail using sophisticatedgain and loss of function models in vitro and in vivo. 2) elucidate the molecular mechanism ofthe regulation of Angiopoietin-2 by HoxB5 - an effect that we have discovered in thepreliminary experiments leading to this proposal. Angiopoietin-2 has been implicated inendothelial cell destabilization, which is a prerequisite of angiogenic sprouting. Thus, HoxBSmay control two key steps in angiogenesis -endothelial cell destabilization and activation. 3)position HoxBS within known vasculogenic and angiogenic signaling cascades using in vitroand in vitro models. We will particularly focus on the regulation of HoxBS by microRNAs asin silico prediction indicates that a microRNA that is involved in blood vessel formation has apotential binding site in the HoxBS gene. The data obtained so far suggest a hierarchicallyhigh position of HoxBS within angiogenetic signaling consistent wilh a key role for HoxBS inblood vessel formation.