Pbx1 transcriptional regulation in renal vascular mural cells

摘要 血流动力在肾脏生理学和病理生理学中起着至关重要的作用，但细胞 和分子机制控制的特殊性质的发展 肾血管床仍然知之甚少。我们最近发现，Foxd1血统， 分化为周细胞、血管平滑肌和肾小球系膜， 在这一过程中起着基础性的作用。具体地说，有条件地消融这个故事 转录因子Pbx1在这个谱系中导致粗大的肾动脉图案缺陷和 突变幼崽的过早死亡。令人惊讶的是，有条件的Pbx1消融并不明显 扰乱肾上皮形态发生。这些数据表明，消融Foxd1中的Pbx1 谱系显示仅由细胞功能异常引起的血管图案缺陷 起源于Foxd1血统。利用小鼠遗传学和最先进的功能成像 在与Peti-Peterdi博士的合作中，我们将研究Pbx1的作用 Foxd1基因谱系的转录调控。在目标1中，我们将确定条件Pbx1 消融会扰乱肾血流动力学。目标2将研究Pbx1-tr调节在 通过Foxd1-衍生物控制血管生成因子的分泌。最后，在目标3中，我们将测试 Pbx1在成熟肾脏中的转录调控是否在其反应中发挥作用 受伤。这些研究结果探讨了粗大肾血管构型的机制 将为设计具有功能血管的肾组织方案提供重要线索 在体外进行工程，并可能启发新的技术来减轻肾脏纤维化，这是一个主要原因 终末期肾病。

SUMMARY Hemodynamic forces play a crucial role in renal physiology and pathophysiology but the cellular and molecular mechanisms controlling the development of the specialized properties of the renal vascular bed remain poorly understood. We recently discovered that the Foxd1 lineage, which differentiates into pericytes, vascular smooth muscle, and the glomerular mesangium, plays a fundamental role in this process. Specifically, conditional ablation of the TALE transcription factor, Pbx1, in this lineage results in gross renal arterial patterning defects and premature death of mutant pups. Strikingly, conditional Pbx1 ablation does not markedly perturb renal epithelial morphogenesis. These data suggest that ablation of Pbx1 in the Foxd1 lineage reveals vascular patterning defects arising solely from the abnormal function of cells derived from the Foxd1 lineage. Using murine genetics and state-of-the art functional imaging techniques in collaboration with Dr. Peti-Peterdi, we will investigate the role of Pbx1 transcriptional regulation in the Foxd1 lineage. In Aim 1, we will determine how conditional Pbx1 ablation perturbs renal hemodynamics. Aim 2 will investigate the role of Pbx1-TR regulation in controlling the secretion of angiogenic factors by Foxd1-derivatives. Finally, in Aim 3 we will test whether Pbx1 transcriptional regulation in the mature kidney plays a role in its response to injury. Results of these studies investigating the mechanisms of gross renal vascular patterning will provide important clues for the design of protocols to functionally vascular renal tissues engineered in vitro and may inspire novel techniques to attenuate renal fibrosis, a major cause of end stage renal disease.