Prox1 and COUP-TFII interactions regulate lymphatic endothelial cell differentiation

Prox1 和 COUP-TFII 相互作用调节淋巴管内皮细胞分化

• 批准号: 10059054
• 负责人: Omar Toubat
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-16 至 2024-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059054
• 关键词: Alanine; Automobile Driving; Back; Basic Science; Binding; Binding Sites; Biological Assay; Biology; Blood Circulation; Blood Vessels; Cardinal vein; Cell Differentiation process; Cell Lineage; Cells; Cellular biology; Chronic; Combinatorics; Complex; Cytoskeleton; Development; Developmental Biology; Disease; Dorsal; Ectopic Expression; Embryo; Embryonic Development; Endothelial Cells; Endothelium; FGFR3 gene; FLT4 gene; Filament; Funding; GTF2I gene; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Heterozygote; Histologic; Homeostasis; ICAM1 gene; IL8 gene; Immune; Individual; Intercellular Junctions; Laboratories; Lead; Liquid substance; Lymph; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Maintenance; Malignant Neoplasms; Mediating; Molecular; Molecular Biology; Mus; Mutation; Nuclear; Pathologic; Pattern; Peripheral; Phenotype; Play; Process; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Regulator Genes; Research Project Grants; Role; Scientist; Signal Pathway; Signal Transduction; Skin; Small Interfering RNA; Specific qualifier value; Specimen; Surgeon; Systems Development; Tamoxifen; Testing; Tissues; Training; United States National Institutes of Health; Vascular Endothelial Growth Factor Receptor-3; Vascular System; Venous; Western Blotting; Work; apoAI regulatory protein-1; cardiogenesis; clinically relevant; cooperative study; density; design; experimental study; homeodomain; in vivo; insight; interest; interstitial; knock-down; lymph flow; lymphatic malformations; lymphatic vasculature; lymphatic vessel; macromolecule; mutant; pressure; programs; promoter; protein protein interaction; response; steroid hormone receptor; synergism; training opportunity; transcription factor

PROJECT ABSTRACT The lymphatic system is a complex vascular and tissue network that transports the lymph fluid containing proteins, macromolecules, and extravasated cells from peripheral tissues back to the circulation. The flow of lymph into lymphatic vessels is largely driven by local changes in interstitial pressure, which signals to lymphatic endothelial cells (LECs) through anchoring filaments in the surrounding extra cellular matrix. In response to increased interstitial pressure, anchoring filaments pull LECs to widen the overlapping cell-cell junctions and allow the flow of lymph into lymphatic vessels. Perturbations in development can lead to congenital lymphatic malformations and malignancies, while disruptions in post-natal lymphatic function can lead to pathologic lymphatic fluid accumulation and chronic immune and digestive problems. Despite the essential role of LECs in lymphatic system development and tissue fluid homeostasis, the signals that specify and maintain LEC identify are not well described. Previous studies have shown that LECs differentiate from venous endothelial cells and that homeodomain transcription factor Prox1 serves as a master regulator of this lineage conversion process. During embryogenesis, a subset of venous endothelial cells of the cardinal vein express Prox1 and migrate out to form rudimentary lymphatic vessels. It is known that these Prox1-positive cells downregulate the expression of genes associated with venous endothelial identify and upregulate gene expression signatures consistent with LECs. However, the exact mechanisms underlying Prox1 mediated LEC differentiation are not known. We previously showed that Prox1 physically interacts with venous endothelial cell fate regulator, COUP-TFII. This preliminary work suggests that in addition to driving venous endothelial cell differentiation, COUP-TFII, also works in concert with Prox1 to establish and maintain the LEC lineage, which is the basis for the hypothesis of the proposed study. The concept that the key molecular regulator of venous endothelial cell identity plays an essential role in lymphatic development is of great interest and highlights the close histogenetic relationship between the two vascular systems. By dissecting the molecular interactions between Prox1 and COUP-TFII during LEC development, this proposal aims to elucidate the gene regulatory networks that orchestrate endothelial cell differentiation and advance our understanding of arteriovenous-lymphatic vascular development and disease.

项目摘要 淋巴系统是一个复杂的血管和组织网络 蛋白质，大分子和外周组织的外外组织的外外细胞回到循环。流的流程 淋巴管中的淋巴在大部分驱动于局部压力的局部变化，这信号向淋巴发信号 内皮细胞（LEC）通过将细丝锚定在周围的额外细胞基质中。响应 增加的间质压力，锚定细丝拉LEC，以扩大重叠的细胞 - 细胞连接和 允许淋巴流入淋巴管。发育中的扰动可能导致先天性淋巴 畸形和恶性肿瘤，而产后淋巴功能的中断会导致病理 淋巴液的积累以及慢性免疫和消化问题。尽管LEC在 淋巴系统发育和组织液稳态，指定和维护LEC的信号识别 没有很好地描述。先前的研究表明，LEC与静脉内皮细胞和 该副域转录因子Prox1是此谱系转换过程的主调节器。 在胚胎发生过程中，基本静脉的静脉内皮细胞的一部分表达prox1并迁移 形成基本的淋巴管。众所周知，这些Prox1阳性细胞下调了表达 与静脉内皮识别和上调基因表达特征相关的基因 lecs。但是，尚不清楚Prox1介导的LEC分化的确切机制。我们 先前表明，Prox1与静脉内皮细胞命运调节剂Coup-TFII物理相互作用。这 初步工作表明，除了驾驶静脉内皮细胞分化外， 与Prox1协同合作以建立和维护LEC血统，这是假设的基础 拟议的研究。静脉内皮细胞身份的关键分子调节剂的概念是 淋巴发育中的重要作用引起了人们的极大兴趣，并突出了密切的组织遗传关系 在两个血管系统之间。通过解剖Prox1和Coup-TFII之间的分子相互作用 在LEC开发期间，该提案旨在阐明协调的基因调节网络 内皮细胞的分化并提高我们对动脉淋巴管发育的理解 和疾病。