Retinal Glial Changes in AMD
Age-related macular degeneration (AMD), the leading cause of blindness in people over 60 years of age, is a complex disease that involves many cells. Two cells that have been largely ignored with regards to AMD are astrocytes and Müller cells, both of which fall into the category of glial cells. Glial cells (also called “glia”) are the most abundant cells in our central nervous system, but are not themselves considered neural tissue; instead, they’re there to provide support and protection for neurons. Since these cells maintain a stable retinal environment and communicate with many cells, disruption to their normal behavior could contribute to the AMD disease process. The proposed research will investigate why glial cells exit the retina in AMD, potentially identifying novel therapeutic targets.
Age-related macular degeneration (AMD) is a leading cause of blindness in people over 60 in the developed world. One area of knowledge about AMD that is severely lacking is about the involvement of cells known as glia, which support retinal function. The goal of my research is to identify glial cell changes in AMD and determine how these may affect AMD progression and treatment. I have observed glial cells forming membranes both above and below the retina in AMD eyes. While many of these membranes are not observed by clinicians, they may alter the efficiency of treatments and also affect the normal retinal function.
For Aim 1 of my study, I am investigating whether glial membranes are observed in areas with AMD pathology. To answer this question, I stain human retinas and choroids with markers for specific proteins to visualize glial cells and blood vessels. I then compare the location of glial membranes above and below the retina to AMD pathology observed in either the stained choroids or photographs taken of the whole eye prior to removing the retina.
I am also looking at the influence of vitreous, the gel-like liquid which separates the retina from the lens, on glial cells. Prior to dissecting the retinas, we collect the vitreous from each eye. Glial cells grown in culture are exposed to diluted vitreous samples taken from the same eyes as the stained retinas. I then analyze the movement and division of cells in response to vitreous. This will determine whether changes to the vitreous in AMD promote glia to exit the retina.
For Aim 2 of this study, I am investigating specific factors that stimulate glial cells to migrate out of the retina. Part of the vitreous samples collected from each eye will be sent to Novartis Institute for BioMedical Research, Inc., where a collaborator on the study will analyze them using SomaScan technology. The SomaScan analyzes up to 5,000 proteins at a time, allowing us to detect changes in many proteins. The vitreous from control eyes will be compared to that from eyes with AMD to determine differences associated with this disease. At the same time, we will be comparing the vitreous from retinas with no glial membranes to that from retinas with membranes. These studies will identify potential novel proteins that may stimulate cells to enter the vitreous.
A second part of Aim 2 is testing the influence of specific proteins which are elevated in AMD on glial cell migration and proliferation in culture. I put cells on a thin membrane with potential stimuli below. After 24 hours, I determine how many cells cross to the other side of the membrane. I am also looking at how these proteins affect the structure of cells and their ability to divide. I will also be testing the influence of proteins identified with our SomaScan analysis.
This study will breach a gap in knowledge regarding the role retinal glia play in AMD pathology. Our collaboration with Johanna M. Seddon, MD, ScM at Tufts provides us the unique opportunity to compare our findings in the laboratory to clinical observations. In addition, I look at human retinas and choroids in the flat perspective, which is not done by many laboratories. The collection of vitreous samples and access to SomaScan technology is also unique and will provide a wealth of data.
The research I am doing will potentially identify novel treatment targets for AMD as well as possibilities for improved treatment efficacy. Furthermore, by identifying potential roles for glial cells in AMD, I hope to increase awareness in the vision research community about the ways in which glial cells may contribute to disease. Since many of the membranes I am observing are subclinical, but could interfere with treatments, the work I am doing may indicate a need for higher resolution clinical imaging in AMD.
About the Researcher
I began doing research as an undergraduate at the University of Michigan, where I studied oxidative stress in relation to fetal alcohol syndrome. I went on to study oxidative stress tolerance in reef sharks as an Honors student at the University of Queensland in Australia. I obtained my PhD degree at Monash University in Victoria, Australia. My PhD research focused on the response of astrocytes to oxidative stress and inflammation on astrocytes in relation to Alzheimer’s disease and stroke. I began my postdoctoral training at the Jackson Laboratory where I learned mouse genetics and molecular biology. During this time, my primary project involved cloning and characterizing a mouse mutant, Lama1nmf223, with abnormal retinal vasculature and astrocyte development. This project sparked my interest in astrocytes and vascular development of the retina. I joined Dr. Jerry Lutty’s laboratory at the Wilmer Eye Institute in 2009, as a post-doctoral fellow, and was promoted to a faculty position as a research associate in 2012. Here, I have continued studying the vascular development in the Lama1nmf223 mice as well as in another mouse which lacks retinal ganglion cells. My work on the Lama1nmf223 mice, along with my past research on astrocytes, has given me a passion for studying retinal glia. I have most recently been looking at glial changes in aged human retinas with and without age-related macular degeneration (AMD). As I begin my independent research career, I plan to focus on closing the gap in our knowledge of retinal glia both in normal aging and disease. I strongly believe that understanding the changes to retinal glia could provide crucial clues to treating many retinal diseases, including AMD.
BrightFocus grants not only fund research that will lead to better treatments for retinal and neurodegenerative diseases, they also boost the careers of many young scientists. As competition for NIH funding increases, it is harder for young investigators to obtain their first grant. Grants from foundations such as BrightFocus enable us to obtain preliminary data, improving the chances for NIH funding. In addition, being funded by a foundation with the high standards of BrightFocus Foundation is a huge confidence builder. For many of us, this is one of our first grants and helps us realize that our ideas are fundable. Without the generosity of BrightFocus donors, many young researchers would not pass the first hurdle in an academic career, which is funding. Therefore, BrightFocus Foundation support can truly be career altering.
First published on: July 19, 2016
Last modified on: June 30, 2019