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Klinik für Augenheilkunde

Retinal Angiogenesis, Makroglia, Stat3 Signaling

Research focus

Retinal vasoproliferative diseases represent common causes of blindness in the western world. Our research focusses on the pathophysiology of retinal vasoproliferative diseases, especially Stat3 signaling as well as the interaction of macroglial and vascular endothelial cells. In a translational approach we combine in vitro and in vivo models with clinical studies to understand the pathophysiology of retinal neovascular diseases.

Stat3 signaling in retinal angiogenesis

Interleukin 6 (IL6)-family cytokines and downstream Jak/Stat3 signaling have been associated with diabetic macular edema, proliferative diabetic retinopathy and age-related macular degeneration. While Stat3 signaling represents a promising therapeutic target in cancer-associated inflammation and angiogenesis, the contribution of IL6-induced Stat3 signaling to retinal neovascular diseases is still poorly understood. IL6-family cytokines seem to differ in their angiomodulatory function suggesting that the effect of IL6-family induced Jak/Stat3 signaling is tightly regulated and strongly context-dependent. We currently focus on characterizing the direct effect of Stat3 activation or knock-down on vascular endothelial cells using proliferation assays, wound healing assays (Figure 1B) and spheroid sprouting assays (Figure 1A). The mouse model of oxygen-induced retinopathy (Figure 1 C), an established rodent model for proliferative retinopathy, is used to assess the effect of IL6-family induced Stat3 signaling in vivo. A Cre/LoxP system with an endothelial specific Cre-line is used to assess retinal angiogenesis under loss of Stat3 signaling during retinal development and the vasoproliferative OIR model. 

Macroglial cells

Astrocytes and Müller glial represent the macroglial cells of the retina. While astrocytes play an important role throughout the entire central nervous system, Müller glial cell are unique to the retina and span all its layers. Next to other important functions including metabolic support to neurons and ion/water transport, Müller cells contribute to the regulation of the blood retinal barrier as well as the angio-modulatory microenvironment.  We use primary Müller cell culture systems to better understand their angiomodulatory secretome under standard and hypoxic cell culture conditions. We are further interested in their role in Stat3-mediated angiomodulation.

Macular Telangiectasia Type 2

Macular Telangiectasia Type 2 (MacTel) is are rare form of maculopathy that slowly deteriorates central vision and therefore strongly affects patients daily life.  As one of three study centers for MacTel in Germany, we enroll patients for the MacTel Project Registry (NHOR) as well as the Phase 3 Renexus (NT-501) clinical trial (NTMT-03). Renexus is an intravitreal implant that continuously secretes ciliary neurotrophic factor (CNTF). CNTF belongs to one of the best studied neurotrophic factors. In a Phase 2 clinical trial, it showed great potential in slowing the disease progression in MacTel. However, the mechanism behind CNTF’s effect in the retina is not fully understood. We study the effect of CNTF on vascular endothelial cells and Müller cells in vitro as well as in vivo. Furthermore, in collaboration with PD Dr. Heinrich we are developing alternative measures to better characterize and assess visual function loss in MacTel patients since visual acuity measurements alone often do not adequately reflect and measure functional limitations in a patient's daily life.

Publications

ORCID ID Felicitas Bucher orcid.org/0000-0003-0081-1420

Principal Investigator

Dr. Felicitas Bucher, MD, Dipl. Vwl.

 

Group Members

Julian Rapp, MD student

Sophie Krüger, technician

 

Collaborations

Dr. Luciana Hannibal, Pädiatrisches Stoffwechselzentrum, Freiburg

PD Dr. S. Heinrich, Sektion Funktionelle Sehforschung

Prof. M. Friedlander, The Scripps Research Institute, San Diego, CA, U.S.A.

Prof. Yea, Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea

 

Funding

Berta-Ottenstein Program for Clinician Scientists

Deutsche Forschungsgemeinschaft (DFG) 

Research Prize of the German Retina Society funded by the Dr. Werner Jackstädt Foundation for basic research in ophthalmology