Pbx1 transcriptional regulation in renal vascular mural cells

总结 血流动力学在肾脏生理学和病理生理学中起着至关重要的作用，但细胞的血流动力学在肾脏病理生理学中起着至关重要的作用。 和控制的发展的分子机制的专门性质的 对肾血管床的了解仍然很少。我们最近发现Foxd 1谱系， 其分化成周细胞、血管平滑肌和肾小球系膜， 在这个过程中起着重要的作用。具体而言，TALE的条件性消融 转录因子Pbx 1在该谱系中导致总体肾动脉图案缺陷， 突变幼崽的过早死亡值得注意的是，条件性Pbx 1消融并不明显 扰乱肾上皮形态发生。这些数据表明，Foxd 1中Pbx 1的消融 谱系揭示了血管图案缺陷仅仅源于细胞功能异常 来源于Foxd 1谱系。利用鼠遗传学和最先进的功能成像技术 技术与Peti-Peterdi博士合作，我们将研究Pbx 1的作用 Foxd 1谱系中的转录调控。在目标1中，我们将确定条件Pbx 1 消融扰乱肾血流动力学。目的2将研究Pbx 1-TR调控在 通过Foxd 1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 成熟肾脏中的Pbx 1转录调控是否在其对 损伤这些研究的结果调查了大体肾血管模式的机制 将为功能性血管肾组织的方案设计提供重要线索 在体外工程，并可能激发新的技术，以减轻肾纤维化，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.