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| Author(s): |
Leila da Silva Magalhães
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2016-06-23 |
| Examining board members: |
Ricardo José Giordano;
Dulcineia Saes Parra Abdalla;
Daniela Sanchez Bassères;
Alexandre Bruni Cardoso;
Nathalie Cella
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| Advisor: | Ricardo José Giordano; Alexander Henning Ulrich |
| Abstract | |
Tie1 is a tyrosine kinase receptor expressed by endothelial cells and important in angiogenesis, the formation of new blood vessels from pre-existing ones. This receptor belongs to a small family of receptors composed of two members only (Tie1 and Tie2) to which angiopoietins have been identified as ligands for Tie2. On the other hand, Tie1 is still an orphan receptor with no ligand identified to date. Thus, it is difficult to assess Tie1 mechanism of action in neovascularization without a known ligand. Nevertheless, gene deletion studies have shown that Tie1 is essential in angiogenesis, and plays an important role in retinal and tumoral vascularization. The aim of our study was to evaluate the participation of Tie1 extracellular domain in angiogenesis, and in the process, to identify putative ligands for this receptor. Utilizing phage display, we have identified and characterized a Tie1 specific and selective ligand peptide, which suggests the existence of a binding site unique to this receptor and not shared by other family members. We show that this peptide prevents endothelial cells proliferation, induced by angiopoetin-1, a ligand for Tie2 but which also modulates Tie1 activity. Using a well-accepted mouse model for human diseases, the oxygen induced retinopathy model, we show that this peptide inhibits angiogenesis in vivo. Since this peptide maps to a unique binding site in Tie1, we hypothesized that it might mimic a natural ligand for this receptor. To identify them, proteins with cross reactive epitopes with an anti-peptide sera were identified by proteomic approaches. These proteins are thus possible ligands for Tie1. In summary, we have shown that Tie1 extracellular domain is important in angiogenesis and we have identified putative ligand for this receptor, which might contribute to a better understanding of the molecular mechanisms associated with Tie1 in blood vessel formation. The peptide here characterized may also be an important tool for the development of novel anti-angiogenesis therapeutic approaches for disesase with an angiogenic component. (AU) | |
| FAPESP's process: | 10/17610-8 - Identification of ligands for tyrosine kinase receptor Tie-1 |
| Grantee: | Leila da Silva Magalhães |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |