Identifying Signals That Draw Immune Cells to Damaged Tissues in Age-Related Macular Degeneration

This project aims to identify the molecules that attract immune cells to damaged tissue in age-related macular degeneration.

In age-related macular degeneration, the outer supporting layer at the back of the eye called the choroid, is damaged. To protect the tissue, immune cells move from blood vessels into the choroid in response to damage. Kelly Mulfaul, PhD, and her colleagues predict that these cells sometimes may do more harm than good and be involved in the death of choroid cells. They plan to explore what draws these immune cells from the circulation into this tissue.

For their studies, the team will evaluate immune molecules that cells produce in response to known stressor molecules in age-related macular degeneration. Using adult stem cells that have been developed into immune cells, Dr. Mulfaul and her team will employ the gene-editing tool CRISPR to remove genes for specific immune proteins and see how this editing affects cell response to the stressors. They also will use other cutting-edge molecular biology tools to examine genetic responses of another type of immune cell in age-related macular degeneration donor tissue samples. The resulting understanding of what draws these immune cells to the choroid at various stages of age-related macular degeneration will support the search for treatments based on the target stress signals.

Early in AMD progression, there is an increased number of activated macrophages in the human donor choroid. The signals involved in the recruitment and activation of choroidal macrophages and their role in choroidal degeneration are yet to be characterized. We will study the mechanism of macrophage recruitment using human AMD iPSC-derived choroidal endothelial cells and monocytes in a co-culture model to begin to understand the pathways regulating immune cell activation in the choroid early in AMD pathogenesis.

AMD is a leading cause of vision loss in aging individuals worldwide. Currently, no therapies exist to prevent or stall the progression of early-stage disease. A thorough understanding of immune cell infiltration and activation at various stages of AMD will aid in drug discovery. By identifying the mechanism responsible for immune cell recruitment in the choroid we will identify chemokine or cytokine molecules that could be targeted and modulated to improve early AMD outcomes.