Role of SHE and ABL signaling in vascular tubulogenesis

SHE 和 ABL 信号在血管生成中的作用

• 批准号: 10587279
• 负责人: Saulius Sumanas
• 金额: $ 63.94万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587279
• 关键词: Adaptor Signaling Protein; Adhesions; Aorta; Biochemical; Biological Assay; Biological Process; Biomedical Engineering; Blood Vessels; Cell Culture Techniques; Cell Separation; Cells; Chemicals; Clinical; Cytoskeletal Modeling; Cytoskeleton; Data; Defect; Development; Diameter; Disease; Dorsal; E protein; Embryo; Endothelial Cells; Event; Family; Genetic; Growth; Human; Knowledge acquisition; Lesion; Maintenance; Modeling; Molecular; Morphogenesis; Mus; Natural regeneration; Organism; Pathologic; Patients; Phosphotransferases; Play; Process; Protein Tyrosine Kinase; Proteins; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tube; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Venous Malformation; Xenograft Model; Xenograft procedure; Zebrafish; cell motility; cell type; experimental study; fluid flow; human disease; improved; inhibitor; malformation; mutant; novel; novel strategies; novel therapeutic intervention; overexpression; regenerative therapy; repaired; rho GTP-Binding Proteins; three dimensional cell culture; tool; vascular bed

Project Summary Formation of vascular lumen of appropriate size, or tubulogenesis, is one of critical steps during vascular development. Many vascular diseases including venous malformations are associated with malformed or enlarged lumens. However, we still have a limited understanding of molecular events that regulate vascular lumen size. Abelson (Abl) kinase signaling regulates diverse processes during development and disease, including cytoskeletal reorganization required for cell morphogenesis, cell motility, adhesion and polarity. Abl signaling in different cell types can induce activation of Rho GTPases, which are known key regulators of lumen formation. However, the role of Abl signaling in regulating vascular lumen size has not been previously investigated. Src homology 2 domain containing E (She) protein was originally identified as a highly conserved factor, which interacted with Abl kinase. We have previously demonstrated that She is specifically expressed in embryonic vasculature in zebrafish embryos. However, its biological function is still unknown in any organism. Here we obtained preliminary data which argues that She acts as a novel regulator of vascular lumen size. Zebrafish mutant embryos deficient in she function display enlarged vascular lumen within the dorsal aorta. Similarly, human vascular endothelial cells, deficient in SHE function, form enlarged tubes. Our preliminary data further suggest that She functions as a novel regulator of Abl signaling, and argue that ABL signaling and lumen formation are misregulated in human venous malformation (VM), suggesting a potential role for ABL and SHE in human disease. We hypothesize that SHE is a novel adaptor protein which functions in the ABL kinase signaling pathway to restrict lumen size during vascular tubulogenesis. We further hypothesize that SHE overexpression may reduce lumen size in VM leading to a novel therapeutic approach. The following specific aims are proposed: 1) Determine the cellular and molecular mechanisms by which She regulates tubulogenesis; 2) Determine if She restricts lumen size by inhibiting Abl kinase signaling pathway; 3) Determine if She overexpression can reduce lumen size in VM. Zebrafish embryos deficient in she function will be analyzed for cellular and molecular defects in vascular tubulogenesis. Conservation of She function will be tested in human vascular endothelial cells. The role of Abl kinase signaling in tubulogenesis and its interaction with She will be analyzed using chemical inhibitors, genetic mutants and biochemical assays in zebrafish embryos and human cells. The therapeutic potential of SHE to reduce the size of vascular lumen will be analyzed in the cell culture and mouse VM model as well as in primary cells isolated from VM patients. Obtained results will identify the role for SHE and ABL signaling during normal and pathological tubulogenesis, which may lead to the development of novel strategies to treat vascular malformations.

项目总结