Project Details
Projekt
Innate immune response in age-related macular degeneration: Inflammasome and microglia activation related to oxidative damage
Subject Area
Ophthalmology
Term
from 2013 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 235216075
Age-related macular degeneration (AMD) is the leading cause of blindness in all industrialized countries. The disease manifests with progressive dysfunction and degeneration of the retinal pigment epithelium (RPE), resulting in secondary photoreceptor loss. The pathogenesis of AMD is incompletely understood but key contributing factors include oxidative damage to the RPE, lipofuscin accumulation within RPE cells, a chronic activation of the innate immune system at the level of the RPE, and eventually RPE degeneration. Our previous DFG-funded project (KR 2863/7-1) identified activation of the NLRP3 inflammasome in RPE cells as a novel molecular link between lipofuscin-mediated photooxidative damage, innate immune activation, and RPE cell degeneration. In particular, we were able to demonstrate that lipofuscin phototoxicity-mediated damage to lysosomal membranes induces NLRP3 inflammasome activation. The resulting cytokine release occured predominantly on the apical (neuroretinal) side of the RPE and induced microglia cell activation and recruitment in vitro.In the proposed follow-up project we plan to verify our in vitro results in an in vivo setting and to evaluate strategies for pharmaceutical inhibition of inflammasome activation in the RPE. We seek to achieve three specific aims: For specific aim 1, we will apply the light-induced retinal degeneration (LIRD) model to Abca4 and Nlrp3 single and double knock out mice to verify that inflammasome activation induced by lipofuscin-mediated photooxidative damage occurs in RPE cells in vivo. For specific aim 2, will employ these mouse models to investigate microglia cell reactivation and recruitment in response to inflammasome activation in detail in vivo. For specific aim 3, we will evaluate two novel therapeutic approaches, deuterated polyunsaturated fatty acids (Retrotope, Los Altos, California) and small molecule NLRP3 inhibitors (IFM Therapeutics GmbH, Bonn) for their capacity to suppress inflammasome activation in RPE cells and its secondary effects. If these substances prove effective in vitro, we plan future projects for their further preclinical assessment in our mouse models in vivo and eventually their clinical evaluation in an investigator-initiated trial.The proposed project will address both basic science and translational aspects of AMD research, thereby providing new insights into immune processes contributing to AMD development as well as preclinical data on new pharmacological substances for therapeutic inhibition of these processes. These results will enhance the understanding of the pathogenesis of AMD and help to identify new treatment approaches for future clinical trials in AMD.
DFG Programme
Research Grants
