Boudreau combines heart disease research projects under new NIH R35

Ryan Boudreau, PhD, associate professor in cardiovascular medicine has received a seven-year, $7.6M R35 NHLBI Emerging Investigator Award (EIA) to support a comprehensive research program examining the genetic and molecular mechanisms underlying heart disease, the global leading cause of death.

Boudreau is one of a few scientists nationwide, and the second at the University of Iowa, to receive an NHLBI R35 EIA. According to the NHLBI, the R35 EIA promotes “scientific productivity and innovation by providing long-term support and increased flexibility” to an investigator with demonstrated and outstanding contributions to the field. This program allows an investigator to take greater risks and pursue research that may benefit from a longer timeframe.

Fueled by this grant, Boudreau’s new program unites three previously independent research projects supported by R01s in the Boudreau Lab into a single, integrated initiative.

Genetics of cardiac risk
The first project continues his research into a common genetic variant that affects the cardiac sodium channel protein NaV1.5, which is essential for initiating the heartbeat. More than one in ten Americans carries this variant, which subtly alters heart rhythm in healthy individuals but dramatically worsens outcomes in those who develop heart failure. Carriers of this variant who suffer a heart attack or have other forms of heart failure face a 50% increase in mortality risk. Boudreau said that he aims to “understand the biological basis of these observations to see if there is something we can do to help in the clinic.” Improvements in treating or managing other conditions such as seizures, sudden death syndromes, Alzheimer’s disease, and pain could also be affected by this research.

Mapping the microRNA regulatory network
The second project delves into the vast, largely uncharted non-coding regions of the human genome, focusing on microRNAs, the small regulatory molecules that fine-tune protein production. “Our genome encodes ~2,000 distinct microRNAs and figuring out which microRNAs regulate which of the 20,000+ protein-coding gene messenger RNAs (mRNA) is a massive, complex puzzle that remains largely unsolved,” Boudreau said. MicroRNAs are increasingly recognized as critical players in cardiovascular disease, with evidence showing that “microRNA levels change with disease and can disrupt normal protein expression, leading to cellular dysfunction.” The lab has already completed high-resolution mapping of microRNA-mRNA interactions in human brain and heart samples. They are now expanding this “body map” to other tissues, which could guide therapeutic development for cardiovascular and neurologic diseases.

Discovering hidden proteins in genomic “dark matter”
The third project investigates microproteins, which are tiny, previously overlooked proteins encoded by regions of the genome once dismissed as “junk DNA.” The Boudreau Lab’s discovery of mitoregulin (Mtln), a microprotein that aids cellular ATP production, has opened new avenues for understanding both cardiac and cancer biology. “Our hearts consume about 13 pounds of ATP per day, roughly 15–20 times their own weight. That’s how energy-demanding this organ is!” Boudreau said. Recent studies demonstrate that mitoregulin stabilizes mitochondrial membranes and protects heart tissue during ischemia-reperfusion injury, a major complication that can occur after a heart attack and stent placement. Beyond the heart, his team recently linked low mitoregulin levels to slower lung cancer cell proliferation and improved cancer patient survival, suggesting it could be an attractive target for cancer therapy.

A unified vision for translational impact
By integrating these three distinct research projects, the new R35 program aims to bridge fundamental discoveries with clinical applications. The grant reflects a growing recognition that the interplay of genetic variants, regulatory RNAs, and newly discovered microproteins holds the key to understanding, and ultimately treating, heart disease at its roots. With this significant investment, the research program is poised to deliver insights that could transform the prevention, diagnosis, and treatment of heart disease for years to come. Boudreau said, “I’m grateful for this award and for my outstanding research team that made this possible. We are excited to see what new discoveries we will make over the next seven years, as this R35 grant will enable us to focus more of our efforts on science.”