Grant: CIHR New Investigator

Age-related macular degeneration (AMD) is the leading cause of blindness in adults over fifty. But little is known about the drivers of new blood vessels that invade the retina in blinding AMD. We do know however that abnormal blood lipid levels and mutations in mitochondria (the cell's powerhouse) are associated with AMD. We therefore suggested that a primary disorder in lipid energy production in the eye might drive abnormal vessel growth, as an attempt to bring more fuel to the retina. Our hypothesis challenges two dogmas in biology: (1) that sugar is the only source of fuel to the eye and, (2) that lack of oxygen is the main driver of blood vessel growth. The eye consumes more energy than any other organ and the retina is a fatty tissue. All enzymes required for energy production from fat are present in the eye. Also, Very low-density lipoprotein receptor (VLDLR) is abundant in the eye. VLDLR facilitates the uptake of fat into cells and is expressed in high energy consuming organs able to use fat as a source of energy, such as the heart. Interestingly, Vldlr knockout (ko) mice develop vascular lesions that mimic a form of AMD. It is a good model in which to test our hypothesis. Vldlrko mice have elevated blood lipid levels because of poor fat uptake. Fat and sugar-derived energy productions are interdependent and regulated in part through lipid receptors. The lipid receptor, GPR40, is highly present in the retina, where its role has not been explored. Our preliminary results suggest that GPR40 controls energy production in the retina. Excess circulating lipids in Vldlrko mice signal through GPR40 to lower sugar uptake resulting in an energy crisis and abnormal vessel growth. Two major gaps in our understanding of AMD are explored. First, the role of lipids as an alternative fuel for the eye. Energy production may be a driving force of AMD. Second, the role of GPR40 as an energy switch in the retina and a possible therapeutic target in AMD.