Project Details
Projekt
Desialylation as trigger of microglia responses in the aging and degenerating retina
Subject Area
Ophthalmology
Molecular and Cellular Neurology and Neuropathology
Molecular and Cellular Neurology and Neuropathology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500260917
Age-dependent retinal degeneration are major causes for vision loss and blindness. A chronic pro-inflammatory environment often orchestrated by microglia is a hallmark of these diseases. Reactive oxygen species (ROS) and complement components (C1q, C3) produced and released by microglia and macrophages have been postulated to contribute to the progression of retinal degeneration. Sialylation is a major checkpoint for the control of the complement system and microglial responses. The amount of sialylation significantly reduces with aging in humans, but its relevance for complement- and microglia-associated disease including age-related macular degeneration (AMD) is unclear. In this project we will study the effect of reduced sialylation on the microglial state in the retina of Gne+/- mice and compare this phenotype to the aging and degenerating human retina in the context of AMD. Gne+/- mice will be crossed with Cx3cr1-GFP reporter animals and mice will be challenged with acute white light exposure. Non-invasive spectral domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy (SLO) will then be used for a controlled temporal analysis of photoreceptor demise and microglia responses in the retina. In addition, we will analyze the sialylation state, microglial phenotype and RNAseq-based transcriptome of human post-mortem retinal tissue derived from AMD patients and aged controls. Combining these in vivo analyses of mice with retinal in situ immunohistochemistry and RNAseq analysis of mice and humans will enable us to define the critical time points when a slight loss of sialylation alerts microglia and triggers retinal degeneration. These experiments can aid to elucidate the relevance of desialylation as trigger of microglia responses in mice and humans during aging and may highlight this biochemical pathway as potential therapy target for age-related retinal diseases.
DFG Programme
Priority Programmes
