PODOPLANIN REGULATION OF LYMPHATIC ENDOTHELIAL CELL IDENTITY IN VIVO

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 淋巴系统起源于血管系统。淋巴管内皮细胞(LECs)从血液内皮细胞(BECs)分化而来，这种谱系决定和LEC表型的维持都是严格受控的过程，这对两个不同的血管间隔的发育和功能是必不可少的。转录因子Prox1是一种促进LEC谱系同一性和抑制BEC表型的二元调节因子。然而，它是如何发挥作用的还不是很清楚。我们观察到，缺乏泊多普宁的小鼠，在LEC中高度表达，表现出充满血液的淋巴管，与特定时间缺失的Prox1(可诱导的Prox1/)小鼠的淋巴管非常相似。我们假设泊多普宁和Prox1一样，在调节内皮细胞特性方面起着关键作用。为了测试这一点，我们提出了两个目标。目的1利用内皮细胞中存在时间特异性的泊多拉宁缺乏的小鼠，确定泊多拉宁控制LEC特性的胚胎和出生后阶段。目的2利用在BECs和LECs中高表达泊多拉宁的转基因品系(Teto-PdpnEC)，在体内确定强制表达泊多拉宁是否抑制BEC的特性。Prox1和泊多拉宁的高表达与具有混合BEC和LEC特征的BEC来源的血管肉瘤的恶变有关。我们将研究在血管内皮细胞系(EOMA和Py-4-1)中过表达泊多拉宁是否会在体内诱导侵袭性血管肉瘤的形成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The lymphatic system originates from the blood vascular system. Lymphatic endothelial cells (LECs) differentiate from blood endothelial cells (BECs), and this lineage decision as well as the maintenance of the LEC phenotype are tightly controlled processes, which is essential for development and functions of the two discrete vascular compartments. The transcription factor Prox1 is a binary regulator that promotes LEC lineage identity and suppresses BEC phenotype. However, how it functions is not well understood. We observed that mice lacking podoplanin, which is highly expressed in LECs, exhibit blood-filled lymphatic vessels that closely resemble those seen in time-specific deletion of Prox1 (inducible Prox1/) mice. We hypothesize that podoplanin, like Prox1, is critical in regulating endothelial cell identity. To test this, we propose two aims. Aim 1 will determine the embryonic and postnatal stages at which podoplanin controls LEC identity using mice with time-specific podoplanin deficiency in endothelial cells. Aim 2 will determine whether forced expression of podoplanin suppresses BEC identity in vivo using a transgenic line that over-expresses podoplanin in BECs and LECs (TetO-PdpnEC). Increased expression of Prox1 and podoplanin is associated with malignant transformation of BEC-derived angiosarcoma with a mixed BEC and LEC identity. We will investigate whether over-expression of podoplanin in endothelial cell lines (EOMA and Py-4-1) induces formation of aggressive angiosarcoma in vivo.