Research Spotlight: Chi Zhang, PhD

Born and raised in Harbin, a city in northeastern China renowned for its spectacular ice sculptures and annual Ice and Snow Festival, Chi Zhang, PhD, developed an early interest in developmental biology. He earned his PhD from Fudan University in Shanghai, where his research focused on the genes that regulate embryonic cardiovascular and kidney development. Upon completing his doctoral training in 2012, Dr. Zhang joined the Harald Junge lab at University of Colorado-Boulder, researching retinal development in the blood-brain/retinal barrier. In February 2019, he joined the Simon John lab at Columbia, where he is now an Associate Research Scientist.

Dr. Zhang recently published his study, “Intraocular pressure induced blood retinal barrier compromise in mouse models and human glaucoma,” in Nature Communications, advancing our understanding of the role the blood-retinal barrier plays in glaucoma. He also recently received a research grant from The Glaucoma Foundation, supporting his project on “Targeting the Blood-Retinal Barrier and NAD+ in Glaucoma,” which further explores how the blood-retinal barrier weakens with the progression of glaucoma and therapeutic strategies to preserve the blood-retinal barrier. From publishing as first author in a top-tier journal to securing his first research grant, Dr. Zhang reflects on his scientific journey and shares the story behind these significant milestones in his research career.

Tell us about yourself. How did you become interested in glaucoma?

My scientific background is in developmental biology, mouse genetics, and retinal vascular biology. I became interested in glaucoma because it is one of the most complex and challenging eye diseases. Although elevated intraocular pressure is a major risk factor, the mechanisms that connect pressure stress to retinal ganglion cell degeneration and vision loss remain incompletely understood.

When I joined the John lab, I realized that my background could help me look at glaucoma from a different angle. Instead of focusing only on pressure or retinal ganglion cells, I became interested in the retinal blood vessels and the environment that supports nerve cells in the eye. I hope this perspective will help reveal new mechanisms of glaucoma and eventually lead to new therapeutic strategies.

What drew you to the John lab?

I was drawn to the John lab because it is internationally recognized for its leadership in glaucoma genetics, disease models, and mechanisms of neurodegeneration. The lab offered an ideal environment for me to bring my background in mouse genetics and retinal vascular biology into glaucoma research and apply it to clinically important questions.

Dr. Simon John has been central to my development as a glaucoma researcher. Following discovery of blood-retinal barrier leakage in glaucoma, he encouraged me to investigate its mechanisms and significance, helping me develop this into a major research direction. He has provided rigorous scientific guidance while also giving me the independence to pursue new hypotheses, build collaborations, and develop my own research program with his mentorship and support. As an Associate Research Scientist, I now lead projects on blood-retinal barrier dysfunction and neurovascular mechanisms in glaucoma, while also mentoring junior researchers and contributing to manuscripts and grant applications.

Tell us about the main findings of your paper “Intraocular pressure induced blood retinal barrier compromise in mouse models and human glaucoma”

Our paper showed that high eye pressure can make some retinal blood vessels subtly leaky in glaucoma. This was not a major bleeding event, but a small breakdown of the blood-retinal barrier, which normally protects the retina by controlling what molecules enter from the blood. We found this leakage in mouse models of glaucoma and in human donor eyes from patients with primary open-angle glaucoma. Importantly, it appeared before obvious damage to retinal ganglion cells, the nerve cells that carry visual information from the eye to the brain. A key finding was that protecting the blood-retinal barrier helped protect retinal ganglion cells and the optic nerve, even without lowering eye pressure. This shows that high eye pressure in glaucoma not only affects nerve cells but also compromises the blood vessel barriers that keep the retina healthy. Protecting the blood-retinal barrier could become a new way to help preserve vision in glaucoma.

How did the idea for this paper come about?

The idea grew from earlier work in the John lab showing that immune cells called monocytes can enter the retina in glaucoma, and that the blood-retinal barrier can be disrupted. However, at that time, the barrier breakdown itself had not been characterized, and it was not known whether protecting this barrier could help prevent vision-related damage.

This led us to ask several questions: When and how frequently does the blood-retinal barrier become leaky? Is this an effect of high IOP? Which blood vessels are affected and does this vary with vessel caliber or location? Does this happen before nerve damage? And most importantly, could protecting the barrier help protect retinal ganglion cells and the optic nerve? These questions became the foundation of the paper.

Is there a particular aspect of the paper you are most proud of?

I am most proud that the study connects a vascular barrier mechanism to glaucoma neurodegeneration in a way that is both mechanistic and translational. We were able to show the disruption in multiple mouse models and in human glaucoma donor eyes. I am also proud that we moved beyond simply describing leakage and began to identify how it occurs, including implicating endothelial transcytosis, a process by which blood vessel cells transport material across the vessel wall.

What is the primary focus of your grant “Targeting the Blood-Retinal Barrier and NAD+ in Glaucoma”?

The primary focus of my Glaucoma Foundation grant is to understand why the blood-retinal barrier becomes weakened in glaucoma and whether this process can be targeted therapeutically. We propose that high eye pressure activates stress-related enzymes in retinal blood vessel cells, leading to energy imbalance and depletion of NAD⁺, a molecule essential for cell metabolism. These changes weaken the BRB and promote retinal cell damage. Using mouse models of glaucoma, we will test whether enzyme inhibition restores barrier function and protects RGCs. This work could uncover a new therapeutic strategy that goes beyond pressure reduction to preserve vision in glaucoma.

Why did you choose to focus on this topic?

We chose to focus on this topic because our earlier work showed that the blood-retinal barrier becomes leaky in glaucoma, but we still needed to understand why this happens. To look for possible mechanisms, we performed RNA sequencing on the leaky retinal vessels. The data showed that many metabolism-related genes and pathways were disturbed. This finding led us to think that high eye pressure may not only physically stress the eye but may also disrupt the energy balance of retinal blood vessel cells. If these cells become metabolically stressed, they may no longer maintain the blood-retinal barrier properly. That is why we began focusing on metabolism and NAD+ biology. We anticipate this work will help explain how the barrier fails in glaucoma and will identify new ways to protect the retina beyond lowering eye pressure.

What were some unique challenges when applying for this grant?

One major challenge was learning how to write a competitive grant during a very difficult funding climate. A strong research idea is not enough. The proposal must clearly explain the significance, innovation, experimental plan, and potential impact in a limited amount of space.

Grant writing was also a new skill that required me to think differently from writing a research paper. I had to anticipate reviewers’ concerns, explain complex science clearly, and show why the work should be supported now. The process was challenging, but it helped me become a more focused writer and a more independent scientist.

What advice would you give other researchers applying for their first grant?

My advice is to start early, revise repeatedly, and seek guidance from an experienced mentor. For my first grant, Dr. Simon John played an important role in helping me identify the strongest central message, improve the logic of the proposal, and anticipate questions reviewers might raise. I first developed and revised the proposal following discussions with Simon, after that Simon and other colleagues provided critical feedback. Their guidance helped me recognize weaknesses that I was too close to the project to see. Good mentorship not only strengthens the application but also teaches you how to think and write more clearly as an independent scientist.

Are there any particular mentors who inspired and guided your journey?

I have been fortunate to have excellent mentors throughout my training. Dr. Harald Junge helped build my foundation in vascular biology and mouse genetics during my postdoctoral training. Dr. Simon John has been especially important in shaping my development as a glaucoma researcher. He encouraged me to pursue my unanticipated findings on blood-retinal barrier dysfunction and gave me the guidance, independence, and resources to develop them into a major research direction. He has taught me how to connect rigorous mechanistic research with disease relevance and has supported my growth in scientific communication, grant writing, mentoring, and career development. His combination of high scientific standards and strong support for independence has helped me develop my own research vision.