Figure 9.

Schematic models of comparative ligandomics, anti-Scg3 therapy, and Scg3 molecular mechanisms. (A) From comparative ligandomics to ligand-based therapy. This study encompasses the initial ligand screening, functional characterization, pathogenic analysis, target validation, and ligand-based therapy to demonstrate the validity and utility of comparative ligandomics. (B) Anti-Scg3 therapy. Scg3 is a unique angiogenic factor that minimally regulates normal ECs. The marked up-regulation of its receptors on diabetic ECs coupled with moderate Scg3 up-regulation in diabetic vitreous exacerbates retinal vascular leakage in DR. Scg3-neutralizing antibody alleviates the leakage by blocking Scg3 binding to its receptor. (C) Scg3 molecular mechanisms. Scg3 activates ERK and Src pathways, but not Akt and Stat3, through unknown receptors. ERK activated by Scg3 and VEGF may regulate different metabolic events (see the Scg3 as a disease-associated angiogenic ligand section of Discussion). FAK, focal adhesion kinase.