Investigation of vascular reorganization in early AMD

• Applicant: Professor Dr. Ulrich Schraermeyer, since 10/2019
• Subject Area: Ophthalmology ; Cell Biology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401013432

My previous work showed that choriocapillaris (CC) loss precedes both dry and wet age-related macular degeneration (AMD) favoring the theory that AMD is initially a vascular disease. However, only in wet AMD is choroidal neovascularisation (CNV) formed as a wound-healing reaction to prevent geographic atrophy by supporting the cessation of CC function. While earlier stages of CNV show predominantly intact vasculature, later stages with overgrowth and leakiness of these vessels induce blinding. All of these findings point to the urgent need for new investigations focusing on the questions of which triggers lead to (1) CC loss, (2) the decision on whether or not CNV is formed in early AMD leading to either the dry or wet form and (3) the induction of leakage of this CNV with late wet AMD?The study proposed aims to investigate the interrelation of the relevant key factors for dry and wet AMD onset and progression by studying their occurrence and effect on choroidal and CNV vessels in AMD affected samples using human donor material, a CNV rat model and a whole eye organ culture model. Particularly, the interrelation of VEGF with other angiogenic/angiostatic growth factors (PEDF, PDGF, angiopoietin l+2), pericyte migration and metabolism as well as extracellular matrix formation with CNV will be investigated in detail. The other already known precursors of AMD, like the thickening of Bruch’s membrane, drusen formation and pigment changes of the RPE, especially relevant for dry AMD, will be further addressed. The methods used will cover multimodal imaging approaches like SLO/OCT and ICG imaging of AMD-related lesions and morphological analysis using immunohistochemistry and electron microscopy. Analytical EM combined with nano secondary ion mass spectrometry will discover areas of iron overload or zinc deprivation which are thought to be a cause of AMD onset and progression. The samples for the animal study will be provided from another project, currently running in parallel.As the donor eyes can only be examined structurally, information about pathomechanisms occurring will be indirect. However, the findings will be correlated to in vivo imaging data obtained from the same donors before death and to data from animal experiments. The benefit of animal experiments in correlation with the donor data is that CNV can be artificially modulated yielding data that cannot be obtained from humans.ln contrast to other studies either focusing on only one marker or late stage AMD tissue, this work will provide a new and important insight into early AMD.Further understanding and knowledge on the triggers that promote dry and wet AMD will be obtained providing new therapeutic strategies. This is important, as there is no approved therapy for dry AMD and it has been found that the anti-VEGF drugs for wet AMD became ineffective after long-term treatment or could lead to geographic atrophy in 40 % of patients after successful treatment.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Antje Biesemeier, until 10/2019