The functional role of the extracellular matrix protein tenascin-C and the interacting matrisome in retinal ischemia/hypoxia

• Applicant: Dr. Jacqueline Reinhard-Recht
• Subject Area: Ophthalmology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516906893

Numerous diseases of the retina, which can lead to severe visual impairments and irreversible blindness, are associated with circulatory disorders, known as ischemia/hypoxia (I/H). Oxidative stress, glial activation, glutamate excitotoxicity, inflammation and apoptosis appear to be the most important pathomechanisms of I/H-associated neurodegeneration. Although advances have been made to better understand the pathomechanism of retinal I/H, the underlying signaling mechanisms are largely unknown and new neuroprotective therapeutic approaches are lacking. In recent years, pivotal evidence has been accumulated indicating that neurodegenerative processes are linked to a remodeling of extracellular matrix (ECM) molecules. ECM molecules create a complex scar environment that seems to have an inhibitory influence on neuronal regeneration. Our preliminary data suggests that retinal ischemia leads to changes of various ECM components in the retina and optic nerve. We were also able to provide initial evidence for a detrimental influence of the ECM glycoprotein Tenascin-C (Tnc) in retinal neurodegeneration. However, the functional role of Tnc and the interacting matrisome in retinal I/H is still poorly understood. The goal of our project is to characterize progressive neurodegeneration and the underlying cellular and molecular mechanisms of Tnc in an ischemia/reperfusion and a hypoxia model. Based on our preliminary findings, we will investigate what influence the loss of Tnc and the matrisome has on the damage to the retina and optic nerve after I/H. We hypothesize (1) that the loss of Tnc and the matrisome leads to neuroprotection of certain retinal cell types. A focus should be on synaptic alterations and glial reactivity after I/H and ECM loss. In this context, we want to analyze whether the loss of Tnc and the matrisome in in Tnc, Tenascin-R und quadruple knock-out mouse lines leads to functional changes in the retina after I/H. Furthermore, we hypothesize (2) that the scar enviroment is restructured after damage. Therefore, we want to focus on the transcriptional/translational regulation of Tnc and the remodeling of the ECM secretome. In addition, we hypothesize (3) that signaling is affected following I/H and ECM loss. Molecular biological, protein biochemical, in vivo as well as multi-omic analyses should unveil changes in the cellular and synaptic compartment, decipher the neuroprotective signaling mechanisms of ECM loss and identify potential biomarkers. Our results will make a significant contribution to the understanding of the molecular pathomechanisms of retinal I/H. In a future perspective, this knowledge could help to develop improved and targeted therapies.

• DFG Programme: Research Grants