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: 10268188
• 负责人: Omar Toubat
• 金额: $ 4.08万
• 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/10268188
• 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; Fluid Balance; Funding; GTF2I gene; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Heterozygote; Histologic; ICAM1 gene; IL8 gene; Immune; Individual; Intercellular Junctions; Laboratories; Lead; Liquid substance; Lymph; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; 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 development; 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，输送含有淋巴液的淋巴液 蛋白质、大分子和外渗细胞从外周组织返回循环。的流量 淋巴液进入淋巴管很大程度上是由间质压力的局部变化驱动的，该变化向淋巴管发出信号 内皮细胞（LEC）通过周围细胞外基质中的锚定丝。作为回应 间质压力增加，锚定细丝拉动 LEC 以加宽重叠的细胞-细胞连接， 允许淋巴液流入淋巴管。发育障碍可能导致先天性淋巴管畸形 畸形和恶性肿瘤，而产后淋巴功能的破坏可能导致病理性的 淋巴液积聚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，指定和维持 LEC 的信号识别 没有得到很好的描述。先前的研究表明LECs由静脉内皮细胞分化而来 同源域转录因子 Prox1 是这一谱系转换过程的主要调节因子。 在胚胎发生过程中，主静脉的一部分静脉内皮细胞表达 Prox1 并迁移出 形成初级淋巴管。已知这些 Prox1 阳性细胞下调表达 与静脉内皮相关的基因识别和上调基因表达特征与 LEC。然而，Prox1 介导的 LEC 分化的确切机制尚不清楚。我们 先前表明 Prox1 与静脉内皮细胞命运调节剂 COUP-TFII 发生物理相互作用。这 初步工作表明，除了驱动静脉内皮细胞分化外，COUP-TFII 还 与 Prox1 协同工作来建立和维持 LEC 谱系，这是以下假设的基础 拟议的研究。静脉内皮细胞身份的关键分子调节剂的概念 在淋巴发育中的重要作用引起了人们极大的兴趣，并强调了密切的组织发生关系 两个血管系统之间。通过剖析 Prox1 和 COUP-TFII 之间的分子相互作用 在 LEC 开发过程中，该提案旨在阐明协调协调的基因调控网络 内皮细胞分化并增进我们对动静脉淋巴管发育的理解 和疾病。