Prox1 and COUP-TFII interactions regulate lymphatic endothelial cell differentiation

项目摘要 淋巴系统是一个复杂的血管和组织网络，其运输含有淋巴液的淋巴液。 蛋白质、大分子和渗出的细胞从外周组织返回循环。的流动 淋巴进入淋巴管主要是由间质压力的局部变化驱动的，这向淋巴管发出信号。 通过在周围的细胞外基质中锚定细丝来刺激内皮细胞（LEC）。响应于 间质压力增加，锚定丝拉动LEC以加宽重叠的细胞-细胞连接， 允许淋巴液流入淋巴管。发育过程中的扰动会导致先天性淋巴结炎 畸形和恶性肿瘤，而出生后淋巴功能的破坏可导致病理性 淋巴液积聚和慢性免疫和消化问题。尽管地方选举委员会在选举中发挥着重要作用， 淋巴系统发育和组织液稳态，指定和维持LEC的信号识别 没有很好地描述。先前的研究表明，LEC从静脉内皮细胞分化， 同源异型域转录因子Prox 1是这一谱系转换过程的主要调节因子。 在胚胎发生期间，主静脉的静脉内皮细胞亚群表达Prox 1并迁移出 以形成基本的淋巴管。已知这些Prox 1阳性细胞下调了 与静脉内皮细胞相关的基因鉴定和上调基因表达特征， LEC。然而，Prox 1介导的LEC分化的确切机制尚不清楚。我们 先前表明Prox 1与静脉内皮细胞命运调节因子COUP-TFII物理相互作用。这 初步研究表明，除了驱动静脉内皮细胞分化，COUP-TFII，也 与Prox 1协同工作，建立和维持LEC谱系，这是假设的基础， 建议的研究。静脉内皮细胞身份的关键分子调节因子在血管内皮细胞中起着重要作用， 在淋巴发育中的重要作用是非常有趣的，并强调了密切的组织发生关系 在两个血管系统之间。通过剖析Prox 1和COUP-TFII之间的分子相互作用， 在LEC的发展过程中，这项建议的目的是阐明基因调控网络， 内皮细胞分化和推进我们对动静脉-淋巴管血管发育的理解 和疾病

PROJECT ABSTRACT The lymphatic system is a complex vascular and tissue network that transports the lymph fluid containing proteins, macromolecules, and extravasated cells from peripheral tissues back to the circulation. The flow of lymph into lymphatic vessels is largely driven by local changes in interstitial pressure, which signals to lymphatic endothelial cells (LECs) through anchoring filaments in the surrounding extra cellular matrix. In response to increased interstitial pressure, anchoring filaments pull LECs to widen the overlapping cell-cell junctions and allow the flow of lymph into lymphatic vessels. Perturbations in development can lead to congenital lymphatic malformations and malignancies, while disruptions in post-natal lymphatic function can lead to pathologic lymphatic fluid accumulation and chronic immune and digestive problems. Despite the essential role of LECs in lymphatic system development and tissue fluid homeostasis, the signals that specify and maintain LEC identify are not well described. Previous studies have shown that LECs differentiate from venous endothelial cells and that homeodomain transcription factor Prox1 serves as a master regulator of this lineage conversion process. During embryogenesis, a subset of venous endothelial cells of the cardinal vein express Prox1 and migrate out to form rudimentary lymphatic vessels. It is known that these Prox1-positive cells downregulate the expression of genes associated with venous endothelial identify and upregulate gene expression signatures consistent with LECs. However, the exact mechanisms underlying Prox1 mediated LEC differentiation are not known. We previously showed that Prox1 physically interacts with venous endothelial cell fate regulator, COUP-TFII. This preliminary work suggests that in addition to driving venous endothelial cell differentiation, COUP-TFII, also works in concert with Prox1 to establish and maintain the LEC lineage, which is the basis for the hypothesis of the proposed study. The concept that the key molecular regulator of venous endothelial cell identity plays an essential role in lymphatic development is of great interest and highlights the close histogenetic relationship between the two vascular systems. By dissecting the molecular interactions between Prox1 and COUP-TFII during LEC development, this proposal aims to elucidate the gene regulatory networks that orchestrate endothelial cell differentiation and advance our understanding of arteriovenous-lymphatic vascular development and disease.