Role of Lipids (Deposits) in Causing Dry AMD

We are characterizing the role of a new protein that is involved in processing lipids, a process that has long been thought to play an important role in macular degeneration. Without the function of this protein, Mouse loses vision and develops lipid deposits that are very similar to the deposits one sees in macular degeneration eyes. In this study, we will explore the relationship of inflammation with this protein in creating these lipid deposits in the eye and will explore the function of this protein in human cell lines to see whether this can serve as a cell culture model of macular degeneration.

The goal of the project is to understand the role of a novel lipid enzyme that makes specific types of omega-3 and omega-6 fatty acids and how this might play a role in macular degeneration. We have made a mouse deficient of this lipid enzyme and found that it accelerates aging in the eye and shows some changes resembling dry AMD. We hypothesize that this mouse could be a novel model to study the mechanism of development of dry AMD. In this grant, we propose to see how the complement system, a pathway implicated in AMD, interacts with this lipid enzyme pathway. We will inhibit complement activity in our mouse model and see how this affects the vision of the mouse. Next, we will look specifically at the role of this lipid enzyme in the retinal pigment epithelium (RPE), a key cell type involved in AMD. Using state-of-the-art gene-editing techniques, we will knock out the function of this lipid enzyme in RPE cells grown in culture and see whether that affects cell death, metabolic function, or aging in these cells. This study will provide a better understanding of how this lipid enzyme affects aging in the eye and how it contributes to the AMD disease process. We expect that the work performed under this proposal will create a solid foundation for future studies to design novel therapeutics that target aging to help treat dry AMD.