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; 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（由适用提供）：淋巴系统通过将间隙液排放回循环中，在组织液体内稳态中起主要作用。淋巴水肿是由淋巴畸形或客观引起的，通常与放射线和手术有关。但是，迄今为止尚无解决潜在分子病理的有效治疗方法。我们最近报道说，9-核视黄酸（RA）可以激活淋巴内皮细胞（LEC）（LEC）的细胞增殖，迁移和管形成，在体内刺激淋巴皮细胞，并改善小鼠模型中的继发性淋巴再生。然而，这些9-CISRA的促淋巴结质特征是非常出乎意料的，因为RAS以其对许多细胞类型的抗增殖作用而闻名，包括血管血管内皮细胞（BEC）。已显示RAS抑制BEC增殖的地方，而RA缺乏小鼠胚胎显示出BEC的过度散射。因此，在此提案中，我们旨在解决两个主要问题（1）RA诱导的淋巴管生成的分子机制是什么，以及（2）RAS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，RAS可能会调节Notch途径以促进淋巴发芽，这表明两个重要的形态学信号之间的新串扰，并且Prox1在RACONCONCONDED的方式中可以在物理上和功能上与RA结构核接收器RxR相互作用Prox1，可以在物理上和功能上与RA-RAN-RAN-RASINGICENT。此外，LECS主要以细胞质RA-Carrier表达FABP4，而PPARγ作为RXR的二聚化伴侣，众所周知，它可以促进对RAS的细胞增殖，而BEC选择性地表达Crabp-II和RARα，RARα，一种诱导RAS的分子配对，可诱导RAS对RAS的响应。 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-proliferating signal to a pro-growth cue in LECs.在这里，我们旨在通过研究RAS在通过RXRα和PPARγ促进淋巴管菌作中的作用来验证这些工作假设（AIM1），《 RAS对血管生成与淋巴管生成的相反影响的机制》（AIM 2），以及RA控制的物理相互作用，以及RA受控的物理相互作用和功能性相互作用，而良好和功能性相互作用和功能性相互作用（AIMX1和RXR-3）（AIM 3）（AIM 3）。总之，我们的研究不仅将提供有关Prox1如何通过充当核接收器的核心节剂作为淋巴发育的主要调节剂的重要信息，而且还定义了RA介导的RA介导的选择性促进淋巴生成的分子机制。从长远来看，我们的研究将有助于奠定基础，以将RAS复制为淋巴循环功能不全的潜在治疗剂。