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（由申请方提供）：淋巴系统通过将组织液引流回循环，在组织液稳态中发挥主要作用。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;然而，迄今为止还没有解决潜在分子病理学的有效治疗方法。我们最近报道9-顺式维甲酸（9-cis retinoic acid，RA）可以激活淋巴管内皮细胞（lymphatic endothelial cells，LECs）的细胞增殖、迁移和管腔形成，刺激体内淋巴管生成，并通过促进淋巴管再生改善小鼠继发性水肿。然而，9-cisRA的这些促淋巴管生成特征是相当出乎意料的，因为已知RA对许多细胞类型具有抗增殖作用，包括血管内皮细胞（BEC）;其中RA已显示出抑制BEC增殖，并且RA缺陷小鼠胚胎显示BEC的过度增殖。因此，在这项提议中，我们的目标是解决两个主要问题（1）RA诱导淋巴管生成的分子机制是什么，以及（2）RA如何选择性地诱导淋巴管生成，同时抑制血管生成。我们的初步研究表明，RA可能通过调节Notch通路促进淋巴管发芽，这表明两个重要的形态发生信号之间存在新的串扰，并且淋巴管分化和发育的主调节因子Prox 1可以以RA控制的方式与RA结合的核受体RXR在物理和功能上相互作用。此外，LEC主要表达作为细胞质RA载体的FABP 4和作为RXR的二聚化伴侣的PPARγ，已知其响应于RA促进细胞增殖，而BEC选择性表达CRABP-II和RARα，这是一种响应于RA诱导细胞生长停滞的分子配对。总之，我们提出了解决我们两个主要问题的工作假设，即（1）RA通过调节LEC中Prox 1和RXR的相互作用来调节Notch途径基因，从而刺激淋巴出芽;（2）LEC中FABP 4和PPARγ的主要表达将RA从抗增殖信号转化为LEC中的促生长信号。在这里，我们的目的是通过研究RA在促进淋巴管生成中的作用，通过RXRα和PPARγ（Aim 1），RA对血管生成与淋巴管生成的相反作用的机制（Aim 2），以及RA控制的Prox 1和RXRα之间的物理和功能相互作用（Aim 3）来验证这些工作假设。总之，我们的研究将不仅提供重要的信息，如何Prox 1功能作为主调节淋巴发育的核受体辅调节，但也定义RA介导的选择性促进淋巴管生成的分子机制。从长远来看，我们的研究将有助于奠定必要的实验基础，重新利用RA作为潜在的治疗剂淋巴循环不足。