A Study to Define the Link between Cell Adhesion and Retinal Ganglion Cell Death

Robert W. Nickells, PhD
University of Wisconsin-Madison (Madison, WI)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2020
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2018166
Award Type:
Standard
Award Region:
US Midwestern

Recipient of the Thomas R. Lee Award for Glaucoma Research.

The Pathological Contribution of Cell Adhesion Disruption in RGC Death

Summary

In order for cells to function normally, they need to make connections with other cells and with their environment. Breaking these connections will cause death. We believe that retinal ganglion cells (RGCs) lose these connections after optic nerve damage and that this may be one of the important initiators of their death in glaucoma. Understanding the importance of the link between ganglion cell connections and ganglion cell death may help us develop ways to prevent this pathology in optic neuropathies like glaucoma. 

Details

The goal of this research is to determine if loss of cell-to-cell, and/or cell-to-surface, contacts by RGCs stimulates the biological pathway leading to their death after damage to the optic nerve.

Cells living in a complex tissue are most healthy when they make and retain contacts with other cells, and to the extracellular environment. We know that tissue culture cells begin to die when we break those contacts. We also know that an early response of RGCs to optic nerve damage, such as you would experience in glaucoma, is to retract their appendages and shrink. A major response of cells to this process is to activate a critical death protein called BAX. We have made technological advances to be able to watch BAX become activated in living RGCs. We found an important feature of this process was their ability to reverse the BAX activation process. The only other time this is known to happen is when cells that have lost their contacts with the outside world manage to reach out and re-establish them again. Our study is focused on determining if the process of BAX activation in RGCs follows the same principles, particularly if specialized signaling pathways associated with cell-cell contact play an important role.

This work will help us understand better how optic nerve damage leads to ganglion cell death. Importantly, the evidence that the process may be reversible provides a possible way to develop a therapy that will rescue damaged cells in patients with glaucoma.

About the Researcher

Rob Nickells was initially trained as a developmental biologist at the University of Calgary, in Calgary Alberta, Canada, where he received his PhD in 1987.  After completing a post-doc in developmental biology at Caltech, he received training in visual sciences, first at Indiana University and later at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine.  At Johns Hopkins, he was involved in the early analysis of the mechanism of cell death in glaucoma in the laboratories of Drs. Donald Zack and Harry Quigley. Since 1994, Dr. Nickells has continued these studies as a faculty member of the Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison. Using mouse models of acute and chronic ganglion cell death, his laboratory has helped identify several points of the cell death pathway that may serve as vital targets for intervention therapies. 

Personal Story

BrightFocus has played a huge role in my success as a scientist. Early on, they provided my first research grant, which helped me start a career in glaucoma research. This was instrumental in kicking off a 25 year (so far!) career studying the molecular biology of how retinal ganglion cells die in this terrible disease. Over the years, I have had the honor of helping this organization evaluate grant applications and distribute countless research awards that play two incredibly important roles in furthering the scientific understanding of glaucoma. First, just as happened with my first award, their research funding help young and promising scientists get a foot hold to start their research careers. Second, and possibly more important, the foundation provides the critical funding required to develop high risk/high reward research projects to scientists of all levels. Because of this, many projects started with BrightFocus funding grow into large programs that are successful in acquiring extramural research support from agencies like the National Eye Institute. This kind of seed funding is a vital element in today's world of limited research funding resources. 

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