Retinoic acid signaling in lymphangiogenesis

淋巴管生成中的视黄酸信号传导

• 批准号: 8614964
• 负责人: Young-Kwon Hong
• 金额: $ 41.06万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8614964
• 关键词: Ablation; Address; Adult; Animal Model; Back; Binding; Biochemical; Biological Process; Blood; Blood Circulation; Blood Vessels; Cancer Patient; Carrier Proteins; Cell Differentiation process; Cell Proliferation; Cells; Cues; Development; Dimerization; Dissociation; Embryo; Enzymes; FABP4 gene; Failure; Foundations; GTP-Binding Protein Regulators; Gene Expression; Genes; Genetic; Growth; Health; Homeostasis; Immune; In Vitro; Intercellular Fluid; Intestines; Knockout Mice; Lipids; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic vessel; Lymphedema; Mediating; Metabolic; Modeling; Molecular; Mus; Natural regeneration; Notch Signaling Pathway; Nuclear Orphan Receptor; Nuclear Receptors; Obstruction; Outcome; Outcome Study; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Postoperative Period; Quality of life; RXR; Radiosurgery; Regulation; Reporting; Retinoic Acid Binding; Role; Seminal; Signal Transduction; Specific qualifier value; Therapeutic; Therapeutic Agents; Tissues; Transcriptional Regulation; Tretinoin; Tube; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-3; Vitamin A; Work; Yeasts; absorption; alitretinoin; angiogenesis; apoAI regulatory protein-1; base; cell fate specification; cell growth; cell type; cellular retinoic acid binding protein; design; effective therapy; fibroblast growth factor receptor 3; gain of function; homeodomain; human NCYM protein; in vivo; insight; loss of function; lymphatic circulation; malformation; migration; molecular pathology; mouse model; notch protein; novel; programs; response; selective expression; trafficking; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): The lymphatic system plays the major role in tissue fluid homeostasis by draining the interstitial fluid back to the circulation. Lymphedema, caused by lymphatic malformation or obstruction, is often associated with radiation and surgery; however effective treatments that address the underlying molecular pathology are not available to date. We have recently reported that 9-cis retinoic acid (RA) can activate cell proliferation, migration and tube formation of lymphatic endothelial cells (LECs), stimulate lymphangiogenesis in vivo, and ameliorate secondary lymphedema by promoting lymphatic regeneration in a mouse model. These pro-lymphangiogenic features of 9-cisRA, however, are quite unexpected, because RAs have been known for their anti-proliferative effects on many cell types, including blood vascular endothelial cells (BECs); where RAs have been shown to suppress BEC proliferation, and RA-deficient mouse embryos display hyper-proliferation of BECs. In this proposal, therefore, we aim to address two main questions (1) what is the molecular mechanism underlying RA-induced lymphangiogenesis, and (2) how can RAs selectively induce lymphangiogenesis, while concurrently suppressing angiogenesis. Our preliminary studies revealed that RAs may regulate Notch pathway to promote lymphatic sprouting, suggesting novel crosstalk between the two important morphogenic signals, and also that Prox1, the master regulator of lymphatic differentiation and development, can physically and functionally interact with a RA-binding nuclear receptor RXR in a RA-controlled manner. Furthermore, LECs predominantly express FABP4 as a cytoplasmic RA-carrier, and PPARγ as a dimerization partner of RXR, which is known to promote cell proliferation in response to RAs, whereas BECs selectively express CRABP-II and RARα, a molecular pairing that induces cell growth arrest in response to RAs. Together, we propose working hypotheses addressing our two main questions that (1) RAs stimulate lymphatic sprouting by modulating Notch pathway genes through regulation of the interactions of Prox1 and RXR in LECs and (2) the predominant expression of FABP4 and PPARγ in LECs converts RA from an anti-proliferative signal to a pro-growth cue in LECs. Here, we aim to validate these working hypotheses by studying the role of RAs in promoting lymphangiogenesis through RXRα and PPARγ (Aim1), mechanism underlying the opposing effects of RAs on angiogenesis vs. lymphangiogenesis (Aim 2), and RA-controlled physical and functional interactions between Prox1 and RXRα (Aim 3). Together, our studies will not only provide important information on how Prox1 functions as the master regulator of lymphatic development by functioning as a nuclear receptor coregulator, but also define the molecular mechanism underlying RA-mediated selective promotion of lymphangiogenesis. In the long run, our study will help lay an essential experimental foundation to repurpose RAs as potential therapeutic agents for lymphatic circulation insufficiency.

描述（由申请人提供）：淋巴系统通过将间质液引回循环系统在组织液稳态中发挥重要作用。由淋巴管畸形或阻塞引起的淋巴水肿通常与放射和手术有关。迄今为止，我们尚不清楚潜在的分子病理学，我们最近报道9-顺式视黄酸（RA）可以激活淋巴管内皮细胞的细胞增殖、迁移和管形成。 (LEC)，刺激体内淋巴管生成，并通过促进小鼠模型中的淋巴再生来改善继发性淋巴水肿。然而，9-cisRA 的这些促淋巴管生成特征是相当出乎意料的，因为 RA 以其抗增殖作用而闻名。许多细胞类型，包括血管内皮细胞 (BEC)；其中 RA 已被证明可以抑制 BEC 增殖，并且 RA 缺陷的小鼠胚胎表现出过度增殖。因此，在本提案中，我们旨在解决两个主要问题（1）RA 诱导淋巴管生成的分子机制是什么，以及（2）RA 如何选择性诱导淋巴管生成，同时抑制血管生成。 RA 可能调节 Notch 通路以促进淋巴萌芽，这表明两个重要的形态发生信号之间存在新的串扰，而且 Prox1（淋巴分化和发育的主要调节因子）可以在物理和功能上与此外，LEC 主要表达 FABP4 作为细胞质 RA 载体，PPARγ 作为 RXR 的二聚化伴侣，已知 RXR 可以响应 RA 促进细胞增殖，而 BEC 选择性地表达。表达 CRABP-II 和 RARα，这是一种响应 RA 诱导细胞生长停滞的分子配对，我们提出了解决两个主要问题的工作假设：(1) RA 通过调节 LEC 中 Prox1 和 RXR 的相互作用来调节 Notch 通路基因，从而刺激淋巴发芽；(2) LEC 中 FABP4 和 PPARγ 的主要表达将 RA 从抗增殖信号转变为 LEC 中的促生长信号。在这里，我们的目标是通过研究 RA 在通过 RXRα 和 PPARγ 促进淋巴管生成中的作用来验证这些工作假设（Aim1），这是相反的机制RA 对血管生成与淋巴管生成的影响（目标 2），以及 RA 控制的 Prox1 和 RXRα 之间的物理和功能相互作用（目标 3），我们的研究不仅将提供有关 Prox1 如何作为淋巴管主调节器发挥作用的重要信息。从长远来看，我们的研究将有助于为 RA 的重新利用奠定重要的实验基础。作为淋巴循环功能不全的潜在治疗剂。