Zu den Inhalten springen

Klinik für Augenheilkunde

Arbeitsgruppe Lange

Research focus

Hypoxia and the innate immunity in neovascular eye disease. Retinal hypoxia has been associated with major causes of blindness including diabetic retinopathy, vascular occlusive disease, age-related macular degeneration and retinopathy of prematurity (Fulton et al., 2009; Stefansson, 2006; Stefansson et al., 2010). A common sequela to retinal hypoxia is the formation of aberrant new vessels which can lead to visual loss by increased vascular permeability causing retinal oedema, vascular fragility leading to haemorrhage, or fibrovascular scarring resulting in retinal detachment (Dorrell et al., 2007). Recent advances in our understanding of the pathogenesis of neovascular eye disease points towards a critical role of the innate immunity for pathological angiogenesis in the eye.

Publications and Webpages

Google-Scholar

Sonderforschungsbereich

www.sfb-trr167.uni-freiburg.de/people/clemens-lange/

 

Projects

Oxygen sensing mechanisms in retinal vascular disease

The aim of this project is to investigate the role of oxygen sensing mechanism and its downstream molecular pathways in the development and progression of ischemic and inflammatory neovascular retinal disease. For this purpose we use two established models for retinal ischemia/hypoxia and inflammation-associated neovascularisation: the oxygen induced retinopathy mouse model and the laser induced choroidal neovascularisation model (Smith 1998, Tobe 1998).

The role of the innate immunity in neovascular eye disease

The aim of this project is to investigate the role of oxygen sensing mechanisms in cells of the innate immunity in the development of pathological ocular neovascularisation. In particular we aim to determine the roles of Hif1a, its downstream effector protein Vegf, and its upstream regulator Vhl, in myeloid cells during the development of retinal and choroidal neovascularisation.  

The innate immunity and hypoxia-inducible transcription factors as potential targets for the treatment of neovascular eye disease

Due to its central role as a master-regulator of responses to hypoxia/ischaemia, Hif is a potentially relevant target for treating neovascular eye disease. The aim of this project is to inhibit the Hif pathway by RNA interference, by direct protein inhibition, or by modifying its degradation by Phd or Vhl in two mouse model of retinal and choroidal neovascularisation.

Methods

Activation of Hifa in the retinal pigmented epithelium induces spontaneous formation of intraretinal and chorioretinal neovascularisation (CNV). Three-dimensional reconstruction of the retinal vasculature and corresponding cryosections of a control and a transgenic mouse in which Hifa is activated in the retinal pigmented epithelium (Lange, Development 2012). RPE= retinal pigmented epithelium, PR= photoreceptors, INL= inner nuclear layer, GCL = ganglion cell layer

In vivo imaging techniques in our laboratory include fundus imaging (A), live cell imaging of fluorescent cells (in this case microglia B), in vivo angiography (C) and optical coherence tomography in rodents (D). RPE= retinal pigmented epithelium, PR= photoreceptors, INL= inner nuclear layer, GCL = ganglion cell layer

The oxygen-induced retinopathy (OIR) mouse model – a model for retinal ischemia and neovascularisation. (A) Experimental setup. (B,C) Retinal flatmount of a control mouse (B) and after OIR induction (C) demonstrating the retinal vasculature (red), retinal neovascularisation (pseudocolored in yellow) and the central area of vasoobliteration and ischemia (outlined in white).

(A) Experimental set up. (B-D) In vivo imaging 7 days after laser CNV induction demonstrating scar formation in the fundus image (B), myeloid cell accumulation around lesion sites (C) and choroidal neovascularisation in the fluorescein angiography (D). Immuno-histochemical staining of an RPE flatmount showing a ring-shaped choroidal nevoascularisation (red) surrounded by cells of the innate immune system (green).

Funding

Deutsche Forschungsgemeinschaft (SFB TR167)

Dr. Jackstädt-Stiftung

Edith-von-Kaulla-Stiftung

Helmut Ecker Stiftung

Grimmke Stiftung

Else-Kröner Fresenius Stiftung

Principal Investigator

 

Prof. Dr. Dr. Clemens Lange
MD, PhD, FEBO

clemens.lange@uniklinik-freiburg.de

 

Group Members

Dr. rer. nat. Anja Schlecht, PhD

Dr. med. Stefaniya Boneva, MD

Markus Gruber, MD

Yannik Laich, MD

Philip Keye, MD

Julian Wolf, MD

Myriam Boeck, MD student

Adrian Thien, MD student

Louis Tenbrock, MD student

Gabriele Prinz, technician

Johannes Baumann, technician

Marc Guder, technician

 

Former Group Members

Peipei Zhang, MD