The neuroprotective role of TGF-beta signaling for photoreceptors

• Applicant: Professorin Dr. Barbara Braunger
• Subject Area: Ophthalmology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 327068312

Age-related macular degeneration and hereditary retinal degeneration are both common causes of vision loss and blindness. In both diseases, vision loss involves apoptotic death of photoreceptors. In previous work, we provided evidence that TGF-beta signaling protects retinal neurons from programmed cell death during development. Our preliminary data strongly indicate that TGF-beta signaling is also neuroprotective for adult retinal neurons and prevents their apoptosis following injury. Based on our published and preliminary data we hypothesize that TGF-beta signaling in the adult eye is required to maintain the constitute expression of neuroprotective factors from Müller glia and/or photoreceptors at sufficiently high levels and that impairment of TGF-beta signaling in the adult eye leads to a higher vulnerability of photoreceptors after injury. The protective effects involve secretion of VEGF from Müller glia and/or photoreceptors. Overall aim of our proposal is to clarify the cell-specific role of TGF-beta signaling in the neuroprotective mechanisms that protect photoreceptors from injury. We will generate and analyze mouse strains to address the question how the cell-specific deletion of TGF-beta signaling in retinal glial cells and/or photoreceptors affects the susceptibility of photoreceptors to apoptotic death using the experimental paradigm of light damage. We will address the question if the increase in TGF-beta signaling after conditional deletion of Smad7 protects photoreceptors from apoptotic death after light damage. We will apply RNAseq to screen broadly and hypothesis-free for signaling networks that might be involved in mediating the protective effects of TGF-beta signaling. Furthermore, we will analyze the expression, amounts and localization of specific neuroprotective molecules in the mouse models before and after light damage. Finally, we will generate a mouse model to analyze if the neuroprotective effects of TGF-beta signaling on photoreceptors are mediated through VEGF.

• DFG Programme: Research Grants