Myeloid cell derived Fibronectin-1 - a novel molecular regulator of neovascular age -related macular degeneration

• Applicant: Dr. Anja Schlecht
• Subject Area: Ophthalmology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542338223

Neovascular age-related macular degeneration (nAMD) is amongst the leading causes of blindness worldwide. The main feature of nAMD is the formation of new blood vessels originating from the choroid and growing into the subretinal space, leading to edema, hemorrhage and finally to irreversible blindness. In recent years, anti-VEGF therapy has enabled significant advances in the treatment of nAMD, but treatment success is compromised by the short half-life of antibodies and therefore repeated intraocular injections are required. In addition, one-third of nAMD patients lose vision despite continuous anti-VEGF therapy, suggesting involvement of other disease-associated molecular mediators and/or cell populations in the progression of nAMD. Subretinal fibrosis, which is characterized by excessive deposition of extracellular matrix components such as Fibronectin1 (FN1), occurs in many nAMD patients and appears to be a likely contributor to disease progression and vision loss despite continuous therapy. FN1 seems to play a key role in this context, as it is a fundamental component of subretinal fibrosis, but also possesses angiogenic properties and may thus promote CNV formation. Preliminary data from my group shows, that myeloid cells, such as resident microglia or infiltrating macrophages, are a major source of FN1 in this process. We hypothesize that microglia- or macrophage-derived FN1 contributes to disease progression by either directly promoting subretinal fibrosis, or by acting as angiogenic factor stimulating CNV. We will address this hypothesis using a combination of human samples, in vivo and in vitro models, single nuclei sequencing to unravel molecular mechanisms as well as translational therapeutic approaches. Using the laser-induced CNV mouse model and human vitreous samples we will determine the kinetics of FN1-expression during CNV and subretinal fibrosis. Microglia- or macrophage-specific FN1 knockout mice will be used to determine if deletion of FN1 in these cells affects CNV formation or subretinal fibrosis. Single nuclei RNA Seq will be employed to unravel involved molecular factors and the cellular microenvironment. To identify the molecular interaction of microglia-derived FN1 and endothelial cells we will perform aortic ring assays in co-culture with FN1-deficient or competent microglia. In a last step we will assess the therapeutic potential of FN1 using the laser-induced CNV model in combination with intraocular injection of anti-FN-1 antibodies. The overall goal of this proposal is to determine the role of FN1-expression during the development of choroidal neovascularization (CNV), its relevance for subretinal fibrosis, to unravel the involved molecular mechanisms and to explore its translational potential as a therapeutical target in the treatment of neovascular age-related macular degeneration.

• DFG Programme: Research Grants