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

描述（由申请人提供）：COUP-TFII 是核受体超家族的成员，在胚胎发育过程中的器官发生中发挥关键作用。在上一个资助期间，我们证明了 COUP-TFII 对于静脉规范和淋巴管形成至关重要。静脉内皮细胞中 COUP-TFII 的缺失使静脉表现得像动脉，而动脉中 COUP-TFII 的错误表达则使动脉变得像静脉一样。这些结果确立了 COUP-TFII 作为静脉规范所必需的第一个转录因子。我们还证明，缺乏内皮细胞 COUP-TFII 的小鼠无法形成原始淋巴囊，从而支持了淋巴内皮细胞源自静脉内皮细胞的百年假设。 COUP-TFII不仅在胚胎发育期间而且在成人中在静脉和淋巴内皮细胞中表达。然而，COUP-TFII 是否是这些血管功能维持所必需的，以及 COUP-TFII 是否在此类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 功能的直接下游靶标，并揭示受 COUP-TFII 影响的信号通路。此外，虽然我们之前的工作表明 COUP-TFII 对于胚胎的血管生成很重要，但我们现在表明 COUP-TFII 对于成人的血管生成也很重要。由于血管生成对于维持肿瘤生长和转移（癌症死亡的主要原因）至关重要，因此评估 COUP-TFII 在肿瘤生长中的作用并剖析其控制血管生成的分子机制至关重要。根据我们的研究结果，我们假设 COUP-TFII 在胚胎发育和成人的血管功能中发挥着关键作用。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.研究COUP-TFII在血管发育和靶基因调控中的作用。我们将确定 COUP-TFII 是否对于维持静脉和淋巴管功能至关重要，并确定介导 COUP-TFII 作用以控制静脉和淋巴管功能的 COUP-TFII 下游靶点。目标 2. 研究 COUP-TFII 在血管生成和肿瘤发生中的作用。我们将确定 COUP-TFII 如何调节成年小鼠的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通常会导致疾病和癌症。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 受体的活性可以通过配体控制，因此我们的研究可能会发现用于潜在血管疾病干预的新治疗药物。

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.