The role of microRNAs in the molecular pathology of neovascular age-related macular degeneration

• Applicant: Professor Dr. Bernhard H.F. Weber, since 4/2018
• Subject Area: Human Genetics
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 337967378

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in industrialized countries. Genome-wide association and large scale re-sequencing studies have identified 34 loci to be associated with AMD risk. Genetic factors conferring disease risk are static factors to which the patient is exposed over his or her lifetime. In contrast, epigenetic markers can rapidly adapt to stimuli such as injury, dietary changes or treatment regimens. Since the retina and other neuronal tissues are difficult to access directly, epigenetic markers present in the blood serum promise to allow a so called liquid biopsy. This type of biopsy would allow the rapid and non-invasive assessment of the state of neuronal tissue injury by simply drawing a blood sample. Recently, we showed that several circulating microRNAs found in blood serum are dysregulated in neovascular AMD and that these microRNAs influence neovascularization in vitro. These microRNAs are highly conserved between man and mouse and are also dysregulated in a laser induced mouse model of neovascular AMD. To extend these first studies, we want to profile the circulating microRNAs of the laser induced mouse model and ascertain the origin as well as targets (genes and pathways) of the circulating microRNAs. Additionally, we plan to characterize the impact of NV AMD associated microRNA modulation in vitro with established assays which reflect relevant disease associated mechanisms like neovascularization, RPE cell death and immune activation. Finally, the potential of circulating microRNAs as therapeutic targets will be evaluated in the NV AMD mouse model by modulating the microRNA expression in the retina and RPE/choroid complex, since previous findings suggested a great potential of a circulating microRNA based therapy on diseases of the vasculature. We plan to modulate the expression of the circulating microRNAs in the retina and the RPE/Choroid complex and to measure the rate of neovascularization. Efficacy and safety will be the main outcome measures of those tests and should serve as a proof-of-concept for future trials in humans.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Felix Graßmann, until 4/2018