Stimulating the Natural Genetic Programs for Survival and Repair of Neurons in Glaucoma

Trent Watkins, PhD
Baylor College of Medicine (Houston, TX)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Glaucoma
Award Amount:
$199,774
Grant Reference ID:
G2019332
Award Type:
Standard
Award Region:
US Southwestern
Trent Watkins, PhD

Stress Signaling in the Survival and Repair of RGCs

Summary

Disease processes in glaucoma harm the connections that allow your eye to send visual information to your brain. This harm stimulates natural repair processes that ultimately fail and even end up further contributing to the loss of vision. Our proposal aims to understand how these repair processes switch from providing hope for recovery to causing greater damage. Appropriate stimulation of these processes may allow for restoration of vision.

Details

My laboratory seeks ways to stimulate the innate repair potential of the retinal neurons that are most affected in glaucoma. These neurons initiate repair programs in response to the injuries they receive during the disease process. In glaucoma, however, these programs actually end up doing more harm them good, even resulting in neuronal death and accelerating the permanent loss of vision. Our first goal is to understand how this response goes from being a potential source of recovery to a major contributor to blindness. Secondly, we aim to unleash the potential of these repair programs, carefully stimulating them in combination with other interventions that are showing early promise for restoring vision. Our approach to achieving these goals centers on the engineering of new genetic tools that allow us to fine-tune the injury response. We can stimulate mild, moderate, or severe responses and change their pattern and timing to determine the precise level of activity that is most beneficial without triggering adverse effects. In the near term, the understanding we gain may reveal the sweet spot, sometimes called a “therapeutic window,” in which drugs that can tame the neuronal injury response might help to prevent the death of retinal neurons in glaucoma. Over the longer term, we seek to coax the innate repair programs of these surviving neurons to help re-establish communication between the eye and the brain for the restoration of vision.

About the Researcher

The road to my current efforts to fight neurodegeneration has involved twists and turns. My first direct involvement in biomedical research career began at the University of North Texas Health Science Center during high school summer breaks, exploring the mechanisms of a DNA repair enzyme. Inspired by the complexities of biochemistry and the remarkable history of scientific breakthroughs in the San Francisco Bay Area, I traveled to Berkeley for undergraduate studies in Molecular and Cell Biology. There I trained in the laboratory of Lasker Award winner Daniel Koshland, Jr., working to develop new approaches for the treatment of Alzheimer’s disease and other dementias. Those efforts set me on the path to a career in Neuroscience. My next stop was graduate studies at Stanford University in the laboratory of Ben Barres, a pioneer in the biology of glia, the support cells that make up the majority of the brain. Though I envisioned a strictly academic career path, I was then enticed by the unique opportunities to pursue postdoctoral research in the laboratory of Marc Tessier-Lavigne at Genentech, Inc. Those studies led to a joint effort with Joe Lewcock to understand the surprising intersection between axon regeneration and neurodegeneration. Following that training, appointment as a Biomarkers Scientist in Early Development at Genentech introduced me to the important challenges of clinical trial design and execution. I am now privileged to incorporate these diverse experiences into my laboratory’s efforts at the Baylor College of Medicine to understand how intrinsic repair programs can help to define the fates of neurons in conditions ranging from glaucoma to spinal cord injury.

Personal Story

I developed an interest in biomedical science at an early age. My mother was diagnosed with the demyelinating disease multiple sclerosis when I was in third grade. Even then, I shared her drive to learn about ongoing research and prospects for treatment. The critical need for therapies to halt her steady decline combined readily with my natural inquisitiveness. By the end of elementary school, I already had my heart set on a career in research. Like many MS patients, visual deficits caused by optic nerve demyelination were a major challenge for my mother. As a result, an opportunity in graduate school to investigate how optic nerve myelin forms and can be repaired was a natural fit. It was not far into my graduate career when the need for improved therapies once again came into sharp focus. My girlfriend, who would later become my wife, underwent grueling treatment for cancer, a disease that would re-emerge a decade later and eventually take her life. Not only did I lose my partner, the world lost a promising young cancer researcher. And I came to understand in even more vivid detail the courage and desperation that accompanies major illness and the crucial role of biomedical research in providing hope for a brighter future. Our battle against my wife’s cancer necessitated twists and turns in the path of my research career, including an unplanned, but exceedingly valuable, experience in drug development. Those experiences inform my laboratory’s approach today. Driven both by scientific curiosity and by the compelling need for new therapies, we continue the legacy of patients and researchers who have inspired us to increase our knowledge and to apply that progress to improve opportunities for recovery.

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