A Nuclear Receptor COUP-TFII in Vascular Function: Angiogenesis and Tumoirgenesis

描述（由申请人提供）：COUP-TFII是核受体超家族的一员，在胚胎发育过程中对器官发生起关键作用。在上一个资助期，我们证明了COUP-TFII对静脉规范和淋巴管形成至关重要。静脉内皮细胞中COUP-TFII的缺失会使静脉表现得像动脉一样，而动脉中COUP-TFII的错误表达会使动脉变成静脉样。这些结果确定了COUP-TFII是静脉规范必不可少的第一个转录因子。我们还证明，缺乏内皮COUP-TFII的小鼠无法形成原始淋巴袋，从而支持了一个世纪以来淋巴内皮细胞来源于静脉内皮细胞的假设。COUP-TFII不仅在胚胎发育期间在静脉和淋巴内皮细胞中表达，而且在成人中也表达。然而，对于这些血管的功能维持是否需要COUP-TFII，以及COUP-TFII是否在这些循环网络功能障碍引起的疾病的发病机制中发挥作用，仍有待确定。为了解决COUP-TFII如何指定和维持血管功能，我们将确定介导COUP-TFII功能的直接下游靶点，并揭示受COUP-TFII影响的信号通路。此外，虽然我们之前的研究表明，COUP-TFII对胚胎血管生成很重要，但我们现在发现，COUP-TFII对成人血管生成也很重要。由于血管生成对于维持肿瘤生长和转移至关重要，是癌症死亡的主要原因，因此评估COUP-TFII在肿瘤生长中的作用并解剖其控制血管生成的分子机制至关重要。基于我们的研究结果，我们假设COUP-TFII在胚胎发育和成人血管功能中起关键作用。为了阐明COUP-TFII如何控制静脉和淋巴功能以及血管生成和肿瘤发生，提出了两个具体目标：目的1。探讨COUP-TFII在血管发育和靶基因调控中的作用。我们将确定COUP-TFII是否对维持静脉和淋巴管功能至关重要，并确定介导COUP-TFII作用控制静脉和淋巴管功能的COUP-TFII下游靶点。目标2。探讨COUP-TFII在血管生成和肿瘤发生中的作用。我们将确定COUP-TFII如何调节成年小鼠血管生成和肿瘤生长，并在离体模型中分析COUP-TFII在细胞生长和肿瘤发生中的功能。最后，我们将确定COUP-TFII在肿瘤发生中的作用，包括功能丧失和功能获得。公共卫生相关性：血液和淋巴管构成主要的循环网络，这些网络的功能障碍往往导致疾病和癌症。在这里，我们建议研究核受体COUP-TFII如何在血管生成和肿瘤发生的背景下调节血管网络的功能。由于COUP-TFII受体的活性可以由配体控制，我们的研究可能会导致发现新的治疗药物，用于潜在的血管疾病干预。

DESCRIPTION (provided by applicant): COUP-TFII is a member of the nuclear receptor superfamily that plays a critical role in organogenesis during embryonic development. In the last funding period, we demonstrated that COUP-TFII is essential for vein specification and lymphatic vessel formation. Loss of COUP- TFII in vein endothelial cells renders the vein to behave like an artery, while mis-expression of COUP-TFII in the artery converts the artery to be vein-like. These results establish COUP-TFII as the first transcription factor essential for vein specification. We also demonstrated that primitive lymphatic sacs fail to form in mice lacking endothelial COUP-TFII, thus supporting the century-old hypothesis that lymphatic endothelial cells are derived from vein endothelial cells. COUP-TFII is expressed in the vein and lymphatic endothelial cells not only during embryonic development but also in the adult. However, whether COUP-TFII is necessary for the functional maintenance of these vessels and whether COUP-TFII plays a role in the pathogenesis of diseases caused by dysfunction of such circulatory networks, remain to be determined. To address how COUP-TFII specifies and maintains vessel function, we will identify the direct downstream targets that mediate COUP-TFII function and uncover the signaling pathways that are impacted by COUP-TFII. In addition, while our previous work showed that COUP-TFII is important for angiogenesis in embryos, we now show that COUP-TFII is also important for angiogenesis in the adult. Since angiogenesis is critical for sustaining tumor growth and metastasis, the major cause of mortality in cancer, it is crucial to assess the role of COUP-TFII in tumor growth and dissect its molecular mechanisms in controlling angiogenesis. Based on our findings, we hypothesize that COUP-TFII plays critical roles in vessel function during embryonic development and in the adult. To elucidate how COUP-TFII controls vein and lymphatic function as well as angiogenesis and tumorigenesis, two specific aims are proposed: Aim 1. Investigate the role of COUP-TFII in vessel development and target gene regulation. We will determine whether COUP-TFII is essential for the maintenance of vein and lymphatic vessel function, and identify COUP-TFII downstream targets that mediate COUP-TFII action to control vein and lymphatic vessel function. Aim 2. Investigate the role of COUP-TFII in angiogenesis and tumorigenesis. We will determine how COUP-TFII regulates angiogenesis and tumor growth in adult mice as well as analyze the function of COUP-TFII in cell growth and tumorigenesis in an ex vivo model. Finally, we will determine the role of COUP-TFII, both loss of function and gain of function, in tumorigenesis. PUBLIC HEALTH RELEVANCE: Blood and lymphatic vessels constitute major circulatory networks, and dysfunctions in these networks often result in diseases and cancers. Here, we propose to study how a nuclear receptor, COUP-TFII, regulates the functions of vascular networks in the context of angiogenesis and tumorigenesis. Since the activity of the COUP-TFII receptor could be controlled by ligands, our studies could lead to discoveries of new therapeutic agents for potential vascular disease intervention.