Mechanism of Decreased Giant Vacuole and Pore Formation in Glaucoma

Haiyan Gong, MD, PhD
Boston University School of Medicine (Boston, MA)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2018
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2016099
Award Type:
Standard
Award Region:
US Northeastern
Haiyan Gong, MD, PhD

Cell-Cell Interaction in Giant Vacuole/Pore Formation

Summary

Normal pressure inside of the eye is maintained through a dynamic balance between the production and drainage of aqueous humor, a fluid that circulates in the front of the eye and bathes the lens.  Higher eye pressure is commonly associated with primary open-angle glaucoma (POAG), a disease that is a leading cause of blindness worldwide. For aqueous humor to drain out of the eye, it needs to exit through a tube called Schlemm’s canal (SC). Two unique structures can be found in the cells that line the wall of SC: giant vacuoles, which are pressure-dependent outpouchings, and pores, which are openings. Previous studies have shown that a reduction in the density of both giant vacuoles and pores occurs in the eyes with POAG, indicating that their scarcity potentially may contribute to the elevated outflow resistance characteristic of this disease. We propose to study two types of cellular interactions in the cells that line SC using a newly developed, advanced 3D electron microscopy technology. The major goal of this project is to determine whether each of these two types of cellular interactions plays a role in regulating aqueous outflow by influencing giant vacuole and pore formation.

Details

Primary open angle glaucoma (POAG), a disease that is a leading cause of blindness worldwide, is commonly associated with higher eye pressure. To understand the causes of this higher eye pressure, we need to first understand the mechanism of how normal eye pressure is produced. Normal pressure inside of the eye is maintained through a dynamic balance between aqueous humor production and drainage. For aqueous humor to drain out of the eye, it needs to exit through a tube, Schlemm’s canal (SC). Two unique structures can be found in the cells that line the inner wall endothelium of SC: giant vacuoles, which are pressure-dependent outpouchings, and pores, which are openings. Previous studies have shown that a reduction in the density of pores occurs in the eyes with POAG, indicating that this reduction can potentially contribute to the elevated outflow resistance characteristic of this disease.

The goal of this project is to investigate two types of cellular connections in the cells that line the inner wall endothelium of SC. We are using a newly developed, advanced 3D electron microscopy technology to determine whether these two types of cellular connections play a role in giant vacuole and pore formation.

Our specific aim 1 is to determine whether a decrease in cellular connections between the inner wall endothelium and its deeper juxtacanalicular connective tissue cells (labeled IW/JCT connections) plays a role in giant vacuole and intracellular pore formation, and whether a decrease in cellular connections between adjacent inner wall endothelial cells (labeled IW/IW connections) promotes paracellular pore formation in normal human eyes.

Our specific aim 2 is to determine whether an increase in the connections between IW/JCT and between IW/IW inhibit the formations of giant vacuoles and pores in human POAG eyes compared to normal human eyes.

The possible role of these two types of cellular connections (IW/JCT and IW/IW) in the inner wall endothelium in modulating aqueous outflow remains unexplored, primarily due to the lack of effective methods to quantify the degree of connectivity. Using serial block-face scanning electron microscopy, we successfully reconstructed 3D geometries of the target cells, giant vacuoles and pores, and the aforementioned connections between IW/JCT and IW/IW. This advanced 3D-EM technology puts us in a pioneering position to quantitatively characterize the effects of changing pressure on cellular connectivity in normal and POAG eyes. Our unique methods enable us, for the first time in glaucoma research, to probe cellular interactions that may contribute to giant vacuole and pore formation and to confirm their role in regulating aqueous humor outflow.

About the Researcher

Haiyan Gong, MD, PhD, is professor of Ophthalmology, Anatomy and Neurobiology at Boston University School of Medicine. She graduated from Jiangxi Medical College, Nanchang, China and received her ophthalmology training and Master’s degree from Peking Union Medical College, Beijing, China. After several years as a practicing ophthalmologist there, she did a one-year research fellowship at West Virginia University in Morgantown, WV. She then received her PhD training in anatomy and neurobiology from Boston University in Boston, MA.

Dr. Gong has been working on the physiology and morphology of the trabecular outflow pathway for more than two decades and has published over 60 articles, invited papers, scientific reviews, and textbook chapters. Her research is focused on understanding the mechanisms that regulate aqueous humor outflow resistance in normal eyes and how this resistance is increased in eyes with POAG, for the purpose of developing insights into new therapeutic strategies to treat this disease.

Personal Story

I received my first BrightFocus Foundation grant in 2001, back when the organization was called the American Health Assistance Foundation. At the time, I was a research assistant professor at Boston University School of Medicine, and trying to build my independent research career. That first funding allowed me to hire a post-doctoral fellow to collect preliminary data for future grant applications. I received additional funding from BrightFocus Foundation from 2005-2009. These three awards have been so valuable for establishing me as an independent researcher in glaucoma and have helped me receive NIH and other industry funding. Additionally, I trained three post-doctoral fellows with these funding, all of them have become clinician scientists, who continue to do research in ophthalmology.  The award I received this year will allow me to hire a research technician to explore a new area using a new technology, which has potential to answer some unexplored questions in the field of glaucoma. I deeply appreciate the support from BrightFocus donors.

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.