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

核受体 COUP-TFII 在血管功能中的作用：血管生成和肿瘤发生

• 批准号: 7891212
• 负责人: SOPHIA Y. TSAI
• 金额: $ 38.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891212
• 关键词: Address; Adult; Aneurysm; Aorta; Arteries; Biological Assay; Blood; Blood Vessels; Cell Cycle Progression; Cells; Collaborations; Complex; Development; Disease; Dorsal; Ectopic Expression; Edema; Embryo; Embryonic Development; Endothelial Cells; Functional disorder; Funding; Gases; Gene Expression Regulation; Genes; Hemorrhage; Homeostasis; Hospitals; Intervention; Ischemia; Knockout Mice; Lead; Ligands; Liquid substance; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Maintenance; Malignant Neoplasms; Mediating; Melanoma Cell; Modeling; Molecular; Mus; Neoplasm Metastasis; Notch Signaling Pathway; Nuclear Receptors; Organogenesis; Pathogenesis; Pathway interactions; Play; Process; Regulation; Role; Signal Pathway; Specific qualifier value; Therapeutic Agents; Tissues; Transgenic Organisms; Vascular Diseases; Veins; Work; Xenograft procedure; angiogenesis; apoAI regulatory protein-1; base; cell growth; cofactor; gain of function; interest; loss of function; malformation; matrigel; member; mortality; network dysfunction; novel; novel therapeutics; public health relevance; receptor; solute; transcription factor; tumor; tumor growth; tumorigenesis

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.

描述（由申请人提供）：COUP-TFII是核受体超家族的成员，在胚胎发育过程中在器官发生中起关键作用。在最后一个资金期间，我们证明了政变 - TFII对于静脉规范和淋巴管形成至关重要。静脉内皮细胞中政变的失去使静脉表现得像动脉一样，而动脉中的政变 - TFII误表达将动脉转化为静脉状。这些结果确立了政变-TFII是静脉规范必不可少的第一个转录因子。我们还证明，原始淋巴SAC在缺乏内皮coup-TFII的小鼠中未能形成，因此支持了百年历史的假设，即淋巴内皮细胞是源自静脉内皮细胞的。 COUP-TFII不仅在胚胎发育期间，而且在成年人中都表达在静脉和淋巴内皮细胞中。但是，政变 - TFII是否对于这些血管的功能维持是必要的，以及政变-TFII是否在由于此类循环网络功能障碍引起的疾病发病机理中起作用，尚待确定。为了解决政府TFII的指定和维护船舶功能的方式，我们将确定介导政府-TFII功能的直接下游目标，并发现受政变-TFII影响的信号通路。此外，虽然我们以前的工作表明coup-tfii对胚胎的血管生成很重要，但我们现在表明coup-tfii对于成年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至关重要，这是癌症死亡率的主要原因，因此评估政变 - TFII在肿瘤生长中的作用并剖析其分子机制在控制血管生成中至关重要。根据我们的发现，我们假设政变-TFII在胚胎发育期间和成年人期间在血管功能中起关键作用。为了阐明政变如何控制静脉和淋巴功能以及血管生成和肿瘤发生，提出了两个具体的目的：目标1。研究政府-TFII在血管发展和靶基因调节中的作用。我们将确定政变 - TFII对于维持静脉和淋巴管功能是否至关重要，并确定介导政府TFII作用以控制静脉和淋巴管功能的coup-tfii下游目标。 AIM 2。研究政变TFII在血管生成和肿瘤发生中的作用。我们将确定政变-TFII如何调节成年小鼠的血管生成和肿瘤生长，并分析政变-TFII在离体模型中的coup-tfii在细胞生长和肿瘤发生中的功能。最后，我们将确定政变-TFII在肿瘤发生中的功能损失和功能增益的作用。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，我们建议研究在血管生成和肿瘤发生的背景下，核受体，政变 - TFII如何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，因此我们的研究可能导致对潜在的血管疾病干预的新治疗剂的发现。