Gene hunting: $2.59M NIH award helps biomedical engineer track origins of heart disease

Every heartbeat depends on a network of proteins working together with remarkable precision. A single genetic mutation can disrupt that balance and eventually lead to heart disease. 

With a $2.59 million National Institutes of Health grant, Jil Tardiff, professor of biomedical engineering and medicine at the University of Arizona, will trace how those changes unfold at the molecular level over the next four years. 

"We've been working toward this research for about 20 years," she said. "It's nice to see these projects culminate in a grant that reflects what we originally built this whole research program around." 

Tardiff and collaborator Steven Schwartz, Regents Professor of chemistry and biochemistry, are zeroing in on hypertrophic cardiomyopathy – a common heart disease that thickens the muscle wall and makes it harder to pump blood. 

Genetic mutations cause an estimated one in 500 people to inherit the disease. While some patients experience only mild symptoms, others develop heart failure or dangerous arrhythmia. 

"We want to understand the molecular events that occur at the very beginning of the disease process," Tardiff said. "If we understand those earliest changes, we can begin thinking about treatments that intervene before the heart has already remodeled."

Following disease from molecule to muscle 

The heart’s microscopic muscle tissue, called the sarcomere, powers every heartbeat. A single gene mutation can alter one amino acid in the sarcomere's proteins – a tiny change that Tardiff and her team are working to understand, tracing how it alters protein behavior and triggers a cascade of molecular changes that can ultimately impair the heart's ability to contract and relax. 

In the Tardiff laboratory, biomedical engineering graduate student Romi Castillo pairs lab experiments with computer models to follow the movement and interactions of heart proteins. Using techniques like time-resolved fluorescence resonance energy transfer (TR-FRET) spectroscopy and molecular dynamics simulations, Castillo and the team measure microscopic changes with light. 

“TR-FRET is a technique that acts as a molecular ruler where we can measure distances between two proteins,” Castillo said. 

Following the chain reaction and identifying where these genetic changes begin will help identify key touchpoints for therapeutic intervention before heart remodeling.

“What excites me most is how we can translate fundamental discoveries about protein structure into potential new therapeutic strategies,” said Castillo. 

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Forging a path for future therapies 

Current treatments for hypertrophic cardiomyopathy target the sarcomere’s thick filament. Tardiff’s findings will be applied to treatment of the thin filament, a group of proteins within the sarcomere that supports heart muscle contraction and relaxation. 

Using insights gained from the team’s structural models, Tardiff has already begun identifying small molecules capable of mending thin filament behavior. 

"We'd love to develop the first therapies that specifically target the thin filament," Tardiff said. "We now have unique tools that allow us to identify new compounds and test whether they can correct the disease mechanisms we're discovering." 

With the NIH award, Tardiff believes the team's years of foundational work have positioned them to make significant advances.

"We've finally reached the point where we can answer many of the questions we've been asking for years. That's incredibly exciting because every answer brings us one step closer to better treatments for patients."