Lipidmetabolism in retinal neovascular disease with emphasize on diabetic retinopathy and age related macular degeneration: role of polyunsuturated fatty acids (PUFA) as therapeutic intervention.

• Applicant: Dr. Raffael Liegl
• Subject Area: Ophthalmology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269524004

Retinal neovascularization (NV) is a major cause of blindness. The cost to society of treating NV with current drugs or ablation therapy is high, stressing our health care system. Yet the economic and human cost of not treating retinopathy is even higher. It is critical to assess effective inexpensive interventions to reduce this disease burden. Although age-related macular degeneration and diabetic retinopathy are characterized by dyslipidemia, little research has been done in lipid metabolism in retinal vascular disease; it is essential to develop this field. This group has previously found a profound beneficial effect of a high omega3 (w-3) vs. omega6 (w-6) polyunsaturated fatty acid (PUFA) diet on retinal NV in oxygen-induced retinopathy (OIR). As PUFA tissue level is dependent on oral intake, (w-3-PUFA is low in european and US diets), adjusting dietary lipids is a compelling way to prevent retinopathy. Retinopathy affects both retinal vessels and neurons and is characterized in part by inflammation. Lipids modulate inflammation and influence angiogenesis and neuroprotection. Potent pro-inflammatory and pro-angiogenic mediators are metabolized from w-6-PUFAs via cyclooxygenase (COX) and lipoxygenase (LOX). Via the same pathways, w-3-PUFAs are metabolized into anti-inflammatory, anti-angiogenic, neuroprotective mediators. It is critical to understand the specific contributions of each of these major lipid metabolizing pathways and identify the exact metabolites that convey the respective effects of w-3 and w-6-PUFAs on retinopathy. Inhibitors or activators of the identified enzymes can then be used to specifically induce or enhance the beneficial effects observed with an w-3-PUFA replete diet. A third major newly discovered family of PUFA metabolizing enzymes, cytochrome P450s (Cyp450s) are independent of COX and LOX and implicated in vasodilation, angiogenesis and inflammation. Little is known about CYP450 w-6- and even less of CYP450 w-3PUFA metabolites with respect to NV or neuroprotection in retinopathy. This area must be explored. Based on our prior work and new preliminary results:We hypothesize that specific w-3 and w-6 PUFA metabolites, processed enzymatically from COX, LOX and Cyp450, mediate both vascular and neuronal homeostasis in OIR and diabetic retinopathy.The proposed experiments will test this hypothesis and identify the specific lipid pathways, their metabolites and the mechanisms by which they alter the severity of retinopathy.

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