Research Spotlight: RNA & Heart Disease Development
Muge Kuyumcu-Martinez, PhD, is a cardiology researcher and a UVA School of Medicine professor of molecular physiology and biological sciences. In their lab, their research is focused on understanding RNA-mediated molecular mechanisms of congenital and adult heart diseases and finding RNA-based treatments for heart disease.
"Mutations in these RNA-binding proteins can lead to specific heart defects," notes Kuyumcu-Martinez. Her group is investigating how RNA-binding proteins control cardiac gene expression during fetal development and in cardiovascular disease. Disruptions of these regulatory pathways contributes to both congenital and adult-onset heart disorders. By defining how these molecular regulators function in healthy hearts and become altered in disease, their work aims to restore normal gene expression and guide the development of more precise, targeted treatments.
Here, they share more about their work on RNA's impact on heart disease.
How Heart Genes are Turned On and Off at the RNA Level
I love the joy in uncovering the mysterious way our heart develops and functions and gives us life. And the best part is I get to do this with brilliant students, postdocs, and trainees. And we get the fulfillment knowing that our work someday will help people with heart disease.
My name is Muge Kuyumcu-Martinez. I'm a professor in the department of molecular physiology and biological physics. My research is centered on RNA binding proteins that control how heart genes are turned on and off at the RNA level. Mutations in these RNA binding proteins can cause specific heart defects such as hypoplastic left heart syndrome, a fatal condition in newborns. It turns out that these RNA binding proteins also are affected when we have poor diet or diabetes.
Our mission is to stop heart disease that affects adults and babies by uncovering how these RNA binding proteins work and shape the development of the heart. We're working on human heart diseases and despite many medications, heart disease is still the number one killer. So we're working towards restoring gene expression and function in diseased hearts more precisely. And we believe that targeting these RNA binding proteins will help achieve these goals. Having the Manning Institute is going to be instrumental for us to turn our molecular discoveries into real treatments by bringing together scientists and state-of-the-art technologies so that we can fight against heart disease.
What are you working on right now?
We're working on heart diseases that affect both newborns and adults with the intention to have effective therapies. Heart disease is the leading cause of death in the U.S.
Our research is mainly centered on RNA-binding proteins that control how heart genes are controlled at the RNA level. Mutations in specific RNA-binding proteins cause birth defects, like hypoplastic left heart syndrome (HLHS), a fatal condition in newborns.
It turns out RNA-binding proteins are also adversely affected by diabetes and poor diet, leading to heart failure.
Our mission is to stop heart disease that affects both newborns and adults. We do that by uncovering how these RNA binding proteins shape the development and function of the heart.
What are the most intriguing potential clinical applications?
Despite many medications, heart disease is still the number one cause of death. We're working towards restoring heart function.
We believe that targeting RNA or RNA-binding protein regulators will help achieve these goals. For example, we have recently discovered an RNA-level switch in a calcium channel that controls its activity. This calcium channel, when mutated, leads to deadly arrhythmias and sudden cardiac death, affecting many Americans (especially athletes). We've designed molecules that trigger this protective switch. We believe these molecules can be effective in controlling this overactive calcium channel and prevent sudden cardiac death.
What do you wish more people knew about your research into RNA & the heart?
Between DNA and proteins sits RNA, one of the most powerful, yet underappreciated, control points in biology. When RNA processing goes wrong in the heart, it leads to disease. We can now intercept and correct these faulty RNAs so that correct proteins are made.
RNA targeting therapeutics have already proven their value in other diseases. Our lab has identified promising targets and is building a translational framework to guide efforts in heart disease.
How did you become interested in this work?
My training started in a lab studying myotonic dystrophy, where I saw firsthand that RNA errors and dysfunctional RNA-binding proteins can directly cause cardiac and skeletal muscle disease. RNA defects themselves were the culprits of disease. Once a year, we would attend conferences where we got to meet the patients. There, I saw the impact of research on patients. This changed everything for me.
I built my own lab focused on RNA-driven mechanisms of adult and congenital heart disease, which was completely understudied at that time. We and others made significant progress addressing RNA-mediated heart disease over the years. Our current work is based on the clinical reality that children with congenital heart defects face repeated surgeries, and many adults with heart failure are running out of options.
Every molecular discovery in our lab is aligned with one question in mind: How does this help a patient? Our RNA biology expertise and ongoing work on identification of new therapeutic targets make our research uniquely positioned to deliver a real impact in combating heart disease.
Why did you choose UVA Health as the place to do your research?
Turning molecular discoveries into therapies requires great science and the right environment. UVA Health has both. Combined with world-class expertise in cardiovascular biology, genetics, cell biology, and RNA biology equipped with outstanding core facilities, UVA is the ideal launchpad for a program built for successful translational outcomes. This is strengthened by having a highly ranked UVA Hospital and outstanding clinicians who serve patients daily. Furthermore, UVA The Manning Institute of Biotechnology will provide dedicated infrastructure for moving discoveries from bench to bedside. Our work alongside clinicians treating heart failure and congenital heart disease patients will ensure our research targets address real clinical needs.
