Project Details
Projekt
Role of complement receptors and microglia in age-related macular degeneration
Applicant
Professor Dr. Thomas Langmann
Subject Area
Ophthalmology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 257498687
Age-related macular degeneration (AMD) is a leading cause of blindness in industrialized countries. Early AMD manifests as drusen deposits between the outer retina and the pigment epithelium. AMD can progress to late stage forms including choroidal neovascularization (CNV) and an atrophic form with macular degeneration of photoreceptors and the pigment epithelium. The etiology of AMD is not completely understood. However, genetic association studies in large patient cohorts and in situ analyses in AMD eyes as well as animal models mimicking some features of AMD have identified an important contribution of dysregulated innate immunity in the eye. Our project of the first funding period of FOR2240 has revealed local dysregulation of complement factors in ocular fluids of AMD patients and found a correlation of disease progression with hyperreflective foci (HF) as potential imaging markers for retinal immune cells. Furthermore, using a light damage paradigm and laser-triggered CNV in mice we established a comprehensive analysis of microglia and macrophages in the retina. Resident microglia-specific targeting of key immune pathways and immunomodulatory compounds could elucidate a vicious cycle of microglia reactivity, retinal degeneration and neoangiogenesis. These findings together provide evidence for an interaction of reactive microglia with aberrant complement proteins in the pathogenesis of AMD. However, the underlying mechanisms that link both systems are only incompletely explored. In this follow-up project we postulate that particularly the anaphylatoxin complement cleavage products C3a and C5a sustain chronic microglia reactivity via receptor-mediated recruitment and activation. We further postulate that hyperreflective foci could potentially mirror complement-regulated microglia responses and may therefore be used to monitor disease development in AMD patients and animal models. The project is subdivided into four specific aims in which we will determined the impact of C3a/C5a anaphylatoxins on microglia in vitro, test the effects of microglial C3a/C5a receptor deficiency in the laser-CNV and light damage models, evaluate the expression and localization of C3aR/C5aR in human retinal sections, and finally correlate the dynamics of hyperreflective foci with ocular complement factors in AMD patients and controls. The results of these studies will provide new insights into the immune-related etiology of AMD and may foster the development of novel effective treatments.
DFG Programme
Research Units
