Targeting the JAK/STAT3 signaling pathway and its inflammatory component in retinal vasoproliferative disease

• Applicant: Dr. Felicitas Bucher
• Subject Area: Ophthalmology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442555235

Vasoproliferative diseases of the retina and associated disorders of the blood-retinal barrier are among the most common causes of visual deterioration in the western world. Currently, there is growing evidence for a major role of inflammation in the development and progression of retinal vascular disease including age-related macular degeneration and diabetic retinopathy. Own studies revealed significantly increased levels of interleukin 6 (IL-6) family related cytokines and their corresponding soluble receptors (e.g. IL6 and sIL6R and IL-11R) in the vitreous of diabetic patients. IL6-family cytokines are strong activators of the JAK/STAT3 signaling pathway. Study results of our current DFG grant suggest that their angiomodulatory effect depends on the presence of membrane-bound vs. soluble receptor components (“cis”- vs “trans”-signaling) triggering distinct intracellular signaling events. The aim of this follow-up research project is to target the JAK/STAT3 signaling pathway on different levels in order to therapeutically modify angiogenesis in retinal vascular disease and further explore the impact of STAT3-associated inflammation on angiogenesis. For this purpose, we will investigate the therapeutic effect of cis- and trans-signaling specific IL6-targeting antibodies as well as JAK/STAT3-targeting small molecule inhibitors on retinal angiogenesis in vitro and in vivo. Angiogenesis assays like the spheroid sprouting assay and the scratch wound assay in vitro and the mouse model of oxygen-induced retinopathy as well as the VLDLR-/- mouse model in vivo will be used to evaluate their angio-modulatory potential whereas transepithelial barrier assays using ARPE-19 and vascular endothelial cells will help to assess their impact on blood retinal barrier integrity. While our current DFG grant focused on the role of STAT3 signaling in vascular endothelial cells, we will now focus on elucidating the role of the JAK/STAT3 signaling pathway in microglia cells and its secondary effect on retinal angiogenesis. Microglia-specific STAT3 knock-down experiments in vitro and in vivo using a CreERTLoxP system will help unravel STAT3’s impact on microglia morphology, function and behavior as well as characterize its secondary effect on angiogenesis in the mouse model of oxygen-induced retinopathy.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Günther Schlunck