Featured Researcher — Brenda Lilly, PhD

Brenda Lilly, PhD, a principal investigator in the Center for Cardiovascular Research at Nationwide Children’s Hospital, examines the interactions between endothelial cells, which line the inside of blood vessels, and smooth muscle cells.

• Studying the NOTCH signaling pathway and its significance in diseases such as diabetes.
• Studying the role of a mutation in the Jagged1 gene (part of the NOTCH pathway) in Alagille syndrome.

Studying endothelial cell dysfunction and the interplay between cell types could lead to a better mechanistic understanding of vascular problems, such as stenosis, in diseases that impact NOTCH pathways. Ideally, once the mechanisms and underlying biology are revealed, clinicians can treat the true cause of disease processes, rather than just the symptoms.

Read on to learn more about Dr. Lilly and her work.

What was your path to your current role?

I got my doctorate at the University of Texas in Houston, then completed postdoctoral research at the University of Utah. After that, I had my first faculty position at the Medical College of Georgia in Augusta and was there for eight years before being recruited to Nationwide Children’s.

I trained as a developmental biologist in a muscle lab and studied muscle cell differentiation. When I came across vascular smooth muscle cells, I thought they were particularly interesting because, unlike other muscle cells types, they can revert to an undifferentiated state especially in disease, so I chose it as my focus.

For example, my lab discovered that NOTCH signaling seems to play a role in diabetes. People with type 2 diabetes have reduced blood flow in their coronary arteries, which is important to their heart health. We have shown that the NOTCH signaling pathway is suppressed in the coronary blood vessels of people with diabetes, and we hypothesize that one reason they don’t function properly is that insulin resistance suppresses NOTCH signaling.

We have submitted a collaborative grant with Aaron Trask, PhD, another principal investigator in the Center for Cardiovascular Research at Nationwide Children’s, to test this hypothesis and uncover the mechanisms behind coronary dysfunction in diabetes. Ideally, if we understand how NOTCH signaling contributes to this decreased blood flow, we can target the pathway therapeutically.

I am also working on NOTCH signaling in Alagille syndrome, an inherited condition that affects numerous body systems and can lead to early death due to organ failure. Most clinicians would immediately think about the liver problems associated with this diagnosis, but another big problem is a vascular phenotype called peripheral pulmonary stenosis, which can lead to significant heart problems. Almost all children with Alagille syndrome have a mutation in the Jagged1 gene, which is part of the NOTCH pathway. We hope to figure out why Jagged1 mutations cause peripheral pulmonary stenosis through collaboration with Vidu Garg, MD, director of the Center for Cardiovascular Research, and Mingtao Zhao, DVM, PhD, who is also a principal investigator in the center. We intend to use patient-derived pluripotent stem cells in the lab to understand what happens with Jagged1 mutations in real patient endothelial and smooth muscle cells as they communicate, proliferate, differentiate and form blood vessels. Until we understand the biology of this disease, we can’t fix it, because we don’t truly know what to target. Once we know what is causing the stenosis, we have a better opportunity to provide effective treatments for these children.

What’s next? 

I love science and my research, and I am always looking for the next big discovery that could change our understanding of a disease or the way we treat patients. I hope to have two grants that will support my work moving forward, and I would like to generate research that results in high-impact publications to advance the field of NOTCH signaling in blood vessels, so we can open up new targets for the medical treatment of challenging diseases.