Cell death mechanisms and glial alterations in an Autoimmune Glaucoma and Ocular Hypertension Model

• Applicant: Professorin Dr. Stephanie Christine Joachim
• Subject Area: Ophthalmology
• Term: from 2009 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 157761286

Glaucoma, characterized through progressive loos of retinal ganglion cells (RGC) and their axons. It is one of the most common causes of blindness in Germany. Until now, glaucoma is treated by lowering intraocular pressure, which leads to a slowed progression, but does not heal. Therefore, research focuses on the currently unknown glaucoma mechanisms. During the last years, it became known that the immune system plays an important role in degenerative processes. Alterations in the antibody pattern were detected in glaucoma patients, for example against heat shock proteins. The meaning of these alterations will be further investigated in this proposal. During the first proposal we could show, that the development of autoreactive antibodies and antibody depositions in the retina occur after immunizing with antigen-homogenates in the autoimmune glaucoma model (EAG). As a consequence, RGC loss and glia cell activation could be observed. Based on these results, RGC death mechanisms in the EAG and the ocular hypertension model (OHT model) will be identified during the first part of the proposal. Another goal is to examine, if glial cell activation or extracellular matrix remodeling are early indicators of cell loss. Subsequently, RGC protection through blockage of different apoptosis-signal-pathways or immunological processes will be analyzed as a therapeutical approach. The apoptosis-cascade as well as the necrosis and autophagy pathway will be analyzed in the EAG and OHT model. Forefronts are the receptors and caspases of the apoptosis-cascade, which are activated through binding of pro-apoptotic cytokines, like TNF-alpha. The question arises, if a ligand-receptor-binding leads to apoptosis and if a certain pathway is preferred. The autophagocytosis, as the special programmed cell death pathway, could play an important role here. Ocular hypertension leads to mechanical damage, which can induce necrotic processes. These unanswered questions regarding the course of events during cell death will be clarified during the second part of the proposal. During the first proposal the existence of autoreactive antibodies was demonstrated. Therefore, the activation of the complement cascade could be possible. The classical, the alternative as well as the lectin pathway will be analyzed. Additionally, both animal models will be combined for the first time, to find out if a combination of risk factors leads to increased cell loss. Should the complement factors contribute to the progression of RGC loss, the therapeutical blockage of the complement system, as an option for cell protection, be analyzed. The findings from this proposal will contribute to a better understanding of the ganglion cell loss mechanisms in glaucoma. This understanding will lead to causal working hypotheses regarding treatment.

• DFG Programme: Research Grants