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Trio of Undergraduate Researchers Seeks To Prevent Leading Cause of Blindness

A trio of University of Virginia fourth-year students are conducting research that aims to understand and prevent one of the leading causes of blindness.

Alyssa Long, Tyler Brobst and Jessica Ungerleider used their 2012 Harrison Undergraduate Research Grants to study “microvascular remodeling” in the retina with Shayn Peirce-Cottler, an associate professor of biomedical engineering in the School of Medicine.

“Pericytes – the cells that enwrap every capillary in our bodies – regulate vascular stability and vascular permeability in the retina,” Peirce-Cottler said. “Pericytes are particularly prevalent in the retinal vasculature, and they are especially important in keeping those blood vessels happy.

“The problem is that in diabetes, pericytes get ‘sick’ and die, so to speak. That leaves the capillaries without their normal covering of pericytes, and causes them to leak and become unstable. Unstable capillaries eventually leads to tearing of the retina, and that is what ultimately leads to blindness in diabetic retinopathy. If we can understand how and why the pericytes become ‘sick,’ we may be able to engineer ways to keep them happy and healthy – even in diabetes,” she said.

This is where the student researchers come in.

“We are focusing on the role of pericytes in the retina,” Long said. “Diabetic retinopathy affects over 100 million people globally, making it the leading cause of blindness. A symptom of diabetic retinopathy is pericyte dropout, so we are studying one of the molecules that we think may be important to pericyte maintenance and vascular stability.”

“Microvascular remodeling” is structural change that occurs in small blood vessels, said Brobst, a biomedical engineering major.

“We are investigating how expression of a certain proteoglycan called neuron-glial antigen 2 (NG2) affects microvascular remodeling in mice,” he said. This molecule is expressed by pericytes, and the team has determined that when it is absent, pericytes are fewer in number and the connectivity of the microvascular beds in the retina is disrupted.

Long, 21, of Downingtown, Pa., a biomedical engineering major with a minor in engineering business in the School of Engineering and Applied Science got involved in the research because of a friend who suffers from Stargardt’s disease, an inherited juvenile form of macular degeneration that causes central vision loss and eventually leads to blindness.

“He manages with great determination and a positive attitude and does not let the disease affect his outlook on life,” Long said. “Seeing what a strong person he is and the obstacles he overcomes on a daily basis motivates me to conduct research that will benefit other inspirational people like him.”

Long began shadowing students in Peirce-Cottler’s lab to learn lab techniques during the spring term of her second year. As a third-year student, she started working with Ungerleider and Brobst with funding from the Harrison Research Grant, and they have continued the research for their engineering capstone project this year.

Brobst, 22, of Woodbridge, came to the research more clinically. 

“I shadowed an ophthalmologist and found eye research to be very interesting,” he said. “I was also drawn to the fact that our research is contributing to the development of a new therapy that could help diabetic patients and prevent vision loss.”

The shared long-term goal of the Peirce-Cottler laboratory and collaborator Dr. Paul Yates, an assistant professor in the Department of Ophthalmology in the School of Medicine, is to develop an adult stem cell-based therapy that replaces the pericytes that are lost in diabetic retinopathy. Long, Brobst and Ungerleider are helping to develop a more foundational understanding of how native pericytes in the retina maintain vascular stability and regulate permeability – and the molecular signals that underpin these functions. And, this knowledge is starting to inform the team’s efforts to use fat-derived stem cells in a mouse model of diabetic retinopathy.

“We need to complete our third aim of injecting adipose-derived stem cells into the murine retina to see if they differentiate into pericytes,” Long said. “We plan to complete our data analysis during the month of April so we have time to compile our results into a paper for a journal submission.”

But more work needs to be done.

“Further preclinical studies need to be carried out in order to evaluate the safety and efficacy of using human adipose-derived stem cells to treat diabetic retinopathy,” Brobst said. From there, clinical trials must be completed successfully before this therapy can be widely used in a clinical setting.

Peirce-Cottler praised the students for their ability to collaborate in high-level science.

“They work very closely together, and, as a team of undergraduates working on what is arguably a graduate-level research project, they function as a finely tuned machine,” she said. “Their project is an innovative combination/extension of two other projects in my laboratory having to do with blood vessel remodeling in the retina – a combination that they conceived of and have been the intellectual leaders for since the project’s inception.”

Long has a better appreciation for the amount of time and effort that goes into research. “We have come a long way from when I started working on this project in my second year, but there are still many more questions to answer,” she said.

After graduation, Long is taking a job with Deloitte Development LLC to develop her business and leadership skills in industry, and wants to work on health care-related projects. Ungerleider plans to pursue similar research while attending graduate school for biomedical engineering, and Brobst will attend Mayo Medical School in Rochester, Minn.

Brobst said the research has given him an appreciation for how lab research can be translated into real therapies that can help patients.

“This idea of translational research is definitely something that I am interested in returning to in the future,” he said. “I have learned a lot about staying organized and working in groups. I have found that I really love working on a team because of the ability to share ideas and attack problems cooperatively. I definitely could not do it on my own.”

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