Attributions

Age-Related Microglia-RPE Interactions in AMD Pathogenesis

Wai Wong, MD, PhD The National Eye Institute

Co-Principal Investigators

Lian Zhao, MD The National Eye Institute

Summary

This proposal tests the hypothesis that cellular interactions between retinal microglia and retinal pigmented epithelial (RPE) cells in the context of aging induce cellular changes at the retinochoroidal interface that promote the progression and advancement of AMD. Elucidating what intercellular communications drive disease pathogenesis will clarify the cell biology of AMD and may discover therapeutic targets for treatment and prevention.

Project Details

At present, knowledge of what causes age-related macular degeneration (AMD) is still incomplete, and as a result, treatments available to prevent and repair vision loss from AMD are still imperfect. Recent studies have discovered that aging as well as the immune system are both important in the development of AMD. In our research, we aim to find out how immune cells in the retina, called microglia, change with aging. We also aim to discover how microgliacontribute to changes in other important cells in the retina affected in AMD. In particular, we will examine how microglia influence the retinal pigment epithelium (RPE), a vital layer of cells altered in “dry” AMD. Also, we will examine how these influences contribute to the growth of aberrant vessels into the retina, the cause of vision loss in wet AMD.

At the conclusion of our study we will be able to obtain important information about how cells interact within the retina to cause the changes seen in AMD. On a scientific level, this will help vision scientists better comprehend how different parts of the retina work together, and how they go awry in disease. On a practical level, understanding these interactions may provide opportunities to therapeutically intervene and control the cellular events driving AMD, achieving effective prevention and treatment of vision loss from AMD.

In our study, we first aim to examine how microglia in the retina undergo aging-related changes in ways that may help us understand how they may drive AMD. Specifically, we are looking carefully at how microglia, as a function of age, produce factors previously thought important in AMD and change in their ability to move to areas affected by AMD. Next, using purified cells in a culture dish, we will examine the interactions between microglia, and RPE cells when they are placed next to each other. We will ask if the union of these two cell types results in the production of factors that are thought to be important in driving AMD. Finally, we will use an experimental mouse model to simulate the union of microglia and RPE cells, a situation also seen in human AMD. By transplanting microglia next to the RPE cell layer in a living organism, we hope to understand how microglia interacts with RPE cells in the retinas of patients with AMD.

In the course of our study, we will employ innovative techniques in cell culture, cell imaging, and cell transplantation to study AMD. Our proposal also directly addresses the question of how biological aging and how changes in the immune system, two important factors in AMD, combine to drive disease. Lessons learned in our proposal have the potential to be translated into novel therapies for AMD prevention and treatment.