Saving Limbs, Saving Lives: Harold Amos Alum Honored for Research into Peripheral Arterial Disease
Ayotunde Dokun, MD, PHD, is an assistant professor of medicine at the University of Virginia Health System in Charlottesville, VA. He is also an alumnus of the Harold Amos Medical Faculty Development program (2009-2013), an initiative funded by the Robert Wood Johnson Foundation (RWJF) that supports faculty in academic medicine and dentistry who are from historically disadvantaged backgrounds.
Human Capital Blog: Congratulations on your recent award from the American Heart Association! What does it mean for your work and for your career?
Ayotunde Dokun: It is a great honor to be recognized by the Peripheral Vascular Council of the American Heart Association with an early stage investigator award. For my work, it means the society recognizes the significance of what I have contributed to the field thus far. For my career, it’s a stepping stone hopefully to a brighter future as physician scientist.
HCB: The award recognizes the research and background of outstanding early-career researchers in the field of peripheral vascular disease. Can you describe your current work in this area?
Dokun: Part of my work in this area has been focused on trying to understand why individuals with peripheral arterial disease (PAD) show different levels of disease severity even when their risk factors and extent of vessel occlusions are similar. Some individuals tend to present with mild symptoms, described as “intermittent claudication,” while others present with a severe form of the disease called “critical limb ischemia.” Individuals with intermittent claudication typically have pain in the affected limb when walking, but this pain is usually relieved when they stop walking. Individuals with critical limb ischemia, on the other hand, tend to have pain even when they are not walking and may have associated ulcer or gangrene in the affected limb.
Such individuals are at a several-fold higher risk of limb amputation and death compared to their counterparts who present with intermittent claudication. Interestingly, similar to what is seen in humans, different strains of mice show different levels of injury when PAD is induced experimentally. We therefore hypothesized that the underlying genetic differences might be contributing to this difference in disease severity.
We explored this possibility using experimentally induced PAD in mice, and our work was the first to identify a region on the mouse chromosome that contained genetic information that, when present, allowed the mice to adapt well to experimentally induced PAD. When absent, it was associated with poor adaption, poor recovery, and a tendency to lose the affected limb. More recently, we have now, for the first time, indentified a specific gene in both mice and humans that modifies the severity of PAD.
HCB: How did you become interested in this disease?
Dokun: As an endocrine fellow at Duke University I was intrigued by the fact that individuals with diabetes are more prone to developing vascular complications. As I explored this area I became aware that this is particularly true in those with PAD. Fortunately, I had the opportunity to train in the laboratory of a cardiologist, Brian Annex, MD, who is considered one of the leaders in the field of PAD research.
HCB: Why are people with diabetes more likely to develop PAD, and why does it tend to be more severe when they do?
Dokun: This is an area that we don’t understand very well. There are a number hypotheses that have been proposed as to why, one of which states that diabetes may accelerate arthrosclerosis, which then leads to vessel occlusion. One possibility why PAD may be more severe among individuals with diabetes is that diabetes may impair normal adaptive processes that occur when a vessel is occluded. Our understanding in this area is quite limited and requires further investigation.
HCB: What role does genetics play in these cases, or what role might it play?
Dokun: Based on our findings, genetics plays a pivotal role in the severity of this disease. Additionally, we also recently showed that hyperglycemia in diabetic individuals impairs part of the normal adaptive processes that follow occlusion of a vessel, and controlling hyperglycemia is critical to normalizing this process following experimentally induced PAD. Therefore, it is very likely that both genetics and the metabolic environment in diabetic individuals interact to dictate disease severity in PAD. This is an area that is currently poorly understood, and I believe the field would benefit immensely from a better understanding of these kinds of interactions.
HCB: You are an alumnus of RWJF’s Harold Amos Medical Faculty Development program. Did that experience help prepare you for this work and, if so, how?
Dokun: Without the support of the Harold Amos Medical Faculty Development program, most of this work would not have been possible. As we all know, scientific research is expensive. The support I received from the Foundation provided the resources necessary for the work and allowed me to have protected time to perform the studies. More than the resources, though, it made me a part of a very special family of investigators. Every time I attended the annual meeting I always came back “charged”— highly motivated to face whatever challenges I am facing in my own work.
HCB: Where will your research take you next?
Dokun: I will continue to explore a more detailed understanding of how the gene we identified contributes to PAD severity in humans. Additionally, I plan to continue to explore what the interaction between the metabolic environment in diabetic individuals and genes, such as the one we just identified, can teach us about how diabetes contributes to PAD severity.