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

描述(申请人提供)：COUP-TFII是核受体超家族的成员，在胚胎发育的器官发生中发挥关键作用。在上一个资助阶段，我们证明了COUP-TFII对于静脉的规范和淋巴管的形成是必不可少的。在静脉内皮细胞中COUP-TFII的缺失使静脉的行为像动脉一样，而COUP-TFII在动脉中的错误表达使动脉变得像静脉一样。这些结果使COUP-TFII成为第一个对静脉规范至关重要的转录因子。我们还证明，在缺乏内皮Coup-TFII的小鼠中，原始淋巴囊无法形成，从而支持了淋巴内皮细胞起源于静脉内皮细胞的百年假说。Coup-TFII不仅在胚胎发育过程中表达于静脉和淋巴管内皮细胞，在成人中也表达。然而，COUP-TFII是否对这些血管的功能维持是必要的，以及COUP-TFII是否在这种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，虽然我们之前的工作表明COUP-TFII对胚胎的血管生成很重要，但我们现在证明COUP-TFII对成人的血管生成也很重要。由于血管生成是维持肿瘤生长和转移的关键，而肿瘤的主要死亡原因是肿瘤的死亡，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。基于我们的发现，我们假设COUP-TFII在胚胎发育和成人的血管功能中发挥关键作用。为了阐明COUP-TFII是如何调控血管和淋巴功能以及血管生成和肿瘤发生的，我们提出了两个目标：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是否是维持静脉和淋巴管功能所必需的，并确定COUP-TFII下游靶点，介导COUP-TFII作用来控制静脉和淋巴管功能。目的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如何调控成年小鼠的血管生成和肿瘤生长，并在体外模型中分析COUP-TFII在细胞生长和肿瘤形成中的作用。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。与公共卫生相关：血液和淋巴管构成了主要的循环系统，而这些系统的功能失调往往会导致疾病和癌症。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受体的活性可以由配体控制，我们的研究可能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.