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Novel mechanisms of vasculogenesis

血管发生的新机制

基本信息

批准号：
10418662
负责人：
Saulius Sumanas
金额：
$ 51.53万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-05 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418662
关键词：
Ablation Atherosclerosis Biological Models Blood Circulation Blood Vessels Cells Data Defect Development Diabetes Mellitus Dyslipidemias Embryo Embryonic Development Endothelial Cells Endothelium Fluorescein Genes Genetic Genetic Recombination Growth Hematopoietic Human Hypertension Image Immunohistochemistry Knowledge Lead Mammals Methods Molecular Molecular Analysis Mus Natural regeneration Organ Phenotype Play Population Pronephric structure Recovery Reporter Role Signal Pathway Site Source Testing Therapeutic Time Tissues Transgenic Organisms Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Endothelium Vascular regeneration Venous Venus Vertebrates Zebrafish angiogenesis base defined contribution in vivo injury and repair intercalation junctional adhesion molecule monolayer mutant novel novel therapeutic intervention progenitor repaired stem cells therapeutically effective transcription factor vascular contributions vascular endothelial dysfunction vasculogenesis

项目摘要

Project Summary Multiple vascular diseases including hypertension, diabetes, atherosclerosis, and others are associated with the dysfunction of vascular endothelium. However, there are currently no effective methods to incorporate new endothelial cells into damaged vessels in vivo which could contribute to vascular regeneration and repair. New blood vessels form by two distinct mechanisms, vasculogenesis, which is differentiation of vascular endothelial cells de novo, and angiogenesis, formation of new vessels by branching from the existing vessels. It is currently thought that vasculogenesis is largely limited to the initial vascular network during embryogenesis, while the majority of the later vessels form by angiogenesis from the existing vasculature. While it is difficult to study vasculogenesis in the mammalian embryos, zebrafish has emerged as an advantageous model system to study vascular development. Molecular mechanisms that control vascular development are highly conserved between all vertebrates including zebrafish and humans. Here we have discovered a novel population of putative vascular progenitors in the zebrafish embryos. These cells show high expression of ETS transcription factor etv2, a known key regulator of vasculogenesis, and are located adjacent to the pronephros (pronephros-associated cells, PACs). Our preliminary data indicate that PACs are the major source of organ specific vasculature, and they contribute to the embryonic vasculature by a novel mechanism of cell intercalation into functional blood vessels. Our data further suggest that PACs are likely conserved in mammalian embryos. In addition, we have identified Junctional Adhesion Molecule Jam2b as one of key regulators required for PAC formation. We hypothesize that PACs are a novel group of multipotent vascular progenitors which provide important contribution for vascular growth. The following specific aims are proposed: 1) Define contribution of PACs to different types of blood vessels; 2) Identify functional role for PACs in vascular development; 3) Identify the role of Jam2b and other upstream regulators in the formation of PACs and vascular development. Lineage tracing approaches will be employed to determine contribution of PACs to different types of vessels in zebrafish embryos. PAC ablation and etv2 conditional inhibition strategies will be used to test the functional role of PACs in zebrafish, and their formation will also be investigated in murine embryos. The role of jam2b in PAC formation, its interaction with Vegf signaling pathway, and functional roles of other PAC-enriched genes will be analyzed in zebrafish. Data obtained in this proposal will answer the key questions regarding the identity and functional role of PACs, and are likely to uncover a novel mechanism of vascular growth. The mechanisms of vasculogenesis are highly conserved, and our preliminary data suggest that similar progenitors are also present in the mammalian embryos. Understanding the mechanism of how PACs form and incorporate into existing vasculature may lead to a new direction to repair damaged vessels for therapeutic purposes.

项目总结