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