Growth Factor Signaling in Eye Development

Douglas Gould, PhD
University of California, San Francisco
Year Awarded:
2017
Grant Duration:
July 1, 2017 to June 30, 2019
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2017218
Award Type:
Standard
Award Region:
US Northwestern
Douglas Gould, PhD

This work requires persistence and patience and often takes many years. Research support is absolutely critical [for] projects that will one day make revolutionary changes to human health.

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Testing Lens-Derived Signaling Pathways in Ocular Dysgenesis

Summary

Normal eye development is a complex process that is poorly understood. People with small developmental defects in the front of the eye are at very high risk of going blind as children or young adults. We are studying genes involved in normal eye development so that we may understand how defects lead to blindness from glaucoma and other diseases, and if there are ways to intervene and prevent vision loss.

Details

The goal of this project is to understand how cells communicate with each other during development in order to form a functional eye.

During development, cells from multiple different origins must work together in a coordinated fashion. In order to coordinate their movements and adopt specialized functions, the cells must communicate with each other. When the molecular signals that they use to communicate are disrupted, the messages are not delivered, and developmental abnormalities occur. In the case of the ocular anterior segment, these developmental abnormalities can lead to elevated intraocular pressure and early-onset glaucoma.

For the first part of our proposal, we are working to identify signals that are sent from the lens to the surrounding tissues that instruct them on how to develop into functional structures of the anterior segment of the eye.

The second part of our proposal concerns the cells that receive the signal – the neural crest cells. Neural crest cells are a special population of multi-functional cells that arose in vertebrates. These cells require context-dependent cues in order to make up most of the structures in the front of the eye. We are studying how these cells integrate molecular messages and how they behave when the messages are not delivered properly. 

The importance of intercellular communication and neural crest cell differentiation have been known for many years. However, the neural crest cell population in the developing eye is very small and that makes it challenging to study. Recent technological advances allow for molecular profiling of small populations of inaccessible cells, and we will use these techniques to compare the molecular signatures of neural crest cells in the developing eye in normal and diseased states.

At the conclusion of our study, we will have a more complete understanding of the molecular events that occur during normal ocular development and what goes wrong in the case of an ocular disease. Understanding how and when developmental abnormalities occur could lead to the identification of potential therapeutic targets for developmental glaucoma.

About the Researcher

Dr. Douglas Gould is a professor and director of research in the Department of Ophthalmology at the University of California, San Francisco, School of Medicine. He earned a PhD in medical genetics from the University of Alberta, in Edmonton, where he studied the role of the FOXC1 genein ocular development and glaucoma, working in the laboratory of Michael Walters, PhD. He then moved to The Jackson Laboratory in Bar Harbor, Maine, to continue studying ocular development and disease in the laboratory of Simon W. M. John, PhD. There he discovered that mutations in the type IV collagen alpha 1 gene (COL4A1) cause a multi-system disorder that includes ocular dysgenesis and glaucoma. Dr. Gould's broad interest is to understand the many biological functions of type IV collagens, their roles in human disease, and how to develop mechanism-based therapies to prevent or reduce the consequences in patients with COL4A1 mutations.

Personal Story

I have always had a strong interest in biological sciences, but even through my early years at university, it was not clear to me how harness this interest. My 'eureka' moment was in the senior year of my undergraduate degree when I heard that the University of Alberta was opening a new department--Medical Genetics. A switch flipped for me. It became unquestionably clear that I was interested in understanding biology as it pertained to human disease, and that understanding how disease occurred was central to developing novel and precise ways to prevent, delay or reduce the impacts to human health. I have been working toward this goal ever since. My main interest is a multi-system congenital disorder that is caused by mutations to two extracellular matrix molecules, COL4A1 and COL4A2. The effects of these mutations can be devastating; however, these are exciting times as we are making great strides in understanding the underlying mechanisms and how we might intervene. This work requires persistence and patience and often takes many years. Research support from BrightFocus Foundation and its donors is absolutely critical to develop and advance projects that will one day make revolutionary changes to human health. 

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