Role of Fuel Deficiency as a Driver of Neovascularization in Age-Related Macular Degeneration

• Applicant: Dr. Bertan Cakir
• Subject Area: Ophthalmology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390146606

The leading cause of irreversible vision loss in the elderly is age-related macular degeneration (AMD). Briefly, AMD can be divided into the atrophic or ‘dry’ and the neovascular or ‘wet’ subtypes. While there is currently no treatment for dry AMD, the progression of the inherently more aggressive subtype of neovascular (nAMD) can be at least slowed with intravitreal injections of anti-vascular endothelial growth factor (VEGF) compounds. Photoreceptors have one of the highest energy needs of any cell type in the body and a decline of mitochondrial function with age is known. Intriguingly, mitochondrial gene mutations are tightly associated with AMD. Fuel shortage in photoreceptor mitochondria could therefore be one of the drivers of pathologic neovessel formation in AMD.Preliminary data acquired at the host institution revealed a novel mechanism contributing to retinal glucose/lipid metabolism and development of retinal neovasuclarization. Three important aspects were uncovered (1) Lipid β-oxidation is an energy source for the retina, (2) GPCR40 (Ffar1) is an important nutrient sensor of circulating lipids that controls retinal glucose entry to match mitochondrial metabolism with available fuel substrates, and (3) nutrient deficiency is a driver of retinal pathological angiogenesis.This research project aims to explore distinct components of the glucose/lipid energy metabolism driving retinal neovasculariszation (NV) and to investigate novel treatment approaches. The involvement of other cell types such as retinal pigment epithelium and Müller cells will be investigated and the contribution of other free fatty acid receptors like GPCR120 will be explored. Newly identified synthetic GPCR40 antagonists will be used to evaluate possible new treatment approaches. To achieve these goals transgenic mouse models will be studied using immunohistochemistry, quantitative PCR and Western blot analysis as well as more complex techniques like quantitative proteomics and vector-based cell-specific genetic modifications.The studies outlined in this proposal will serve to test a new paradigm of glucose and lipid energy metabolism as possible drivers of retinal neovascularization. Current anti-VEGF therapy is successful in treating end stage NV in AMD patients but may compromise retinal neurons and vasculature and does not address the root of the problem. Effective prevention of pathologic NV in AMD has broad translational value. Clearer understanding of the underlying disease pathology in neovascular AMD and identification of effective preventative treatment options will ultimately benefit patients

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Lois Smith, Ph.D.