Debold Receives $2 Million ‘Outstanding Researcher’ Award From NIH
Grant will support advances in molecular motor research
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Professor of Kinesiology Edward “Ned” Debold has received a five-year, $2 million grant from the National Institutes of Health (NIH) to advance his research on how myosin molecules—molecular motors crucial for muscle contraction—work together to drive different processes within cells.
This multi-pronged research will lead to a better understanding of many important myosin-related functions, from how our muscles and heart contract to how the ear’s stereocilia facilitate hearing. The long-term goal is to use these findings to pinpoint the causes of dysfunction in myosin-associated diseases and to identify targets to treat certain forms of heart failure and neurological disorders, as well as genetic forms of deafness.
“Most people are familiar with myosins in our muscles, where these tiny little molecules—20 nanometers in size—coordinate their behavior so we can pick up a glass of milk or a dumbbell or walk across the street,” says Debold. “We have trillions of them in our muscles where nanoscale motions allow us to move.”
Beyond their better-known role in muscle contraction, myosins constitute a “superfamily of proteins” that convert chemical energy into mechanical work within a cell, carrying out roles essential for life, like transporting important chemical messengers or helping to form structures that allow us to hear.
Debold’s R35 grant is an NIH National Institute of General Medical Sciences’ Maximizing Investigators’ Research Award (MIRA) that targets scientists “with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential,” according to the NIH.
In his Muscle Biophysics Lab in the first part of the project, Debold will work on fully characterizing how a single myosin responds to an applied load to help understand how teams of the molecules work together to cause muscles to contract and cells to move intracellular cargo. He will share these data with his collaborators Sam Walcott, a professor of applied mathematics at Worcester Polytechnic Institute, and Christopher Yengo, professor and chair of cell and biological systems at Penn State University College of Medicine.
“When myosin motors work as a team, unusual behaviors happen,” Debold says. “We have a hypothesis that if we could fully characterize one of these motors at the single molecule level, we could build models to determine how they drive complex processes inside a cell. These models will then be directly tested using our mini-ensemble laser trap assay, which measures the force-generation of small teams of myosins.”
Debold compares the actions of a single motor versus a team of myosin motors to those of a single person in a scull versus a team of rowers. “A team of rowers must coordinate their activity to move effectively,” he says, “and this allows them to go faster than a single rower in a scull. And they might move in different ways and their velocity might change when they are part of the team.”
Studying and understanding how myosin teams normally function will shed light on the cause and outcome of myosin dysfunction. “In disease states, the team of motors somehow misbehaves, so the question is how can we tweak the system to get it to behave normally and restore normal function?” Debold says.
Walcott will create mathematical models of myosin behavior based on Debold’s data. “I can see high-level things going on, such as a change in velocity or change in force, but he can model that and provide much more molecular detail. That would be extremely helpful for identifying drugs that would target myosin, because it could reveal the exact step or steps in the biochemical cycle to target with a drug,” Debold says.
In another part of the research, Debold and team will examine myosin 3, a distant cousin of muscle myosin that is involved in the formation of stereocilia in human ears. The movement of these structures allows the brain to process hearing. Mutations in myosin 3 can cause deafness, but it is not understood how this occurs. Gaining an understanding of how myosin 3 functions in stereocilia could eventually lead to the development of a drug to treat this form of deafness.
Debold also will study myosin 5, which serves as a transporter in cells. In the nervous system, myosin 5 moves synaptic vesicles to the tips of nerve cell axons, creating a ready supply of neurotransmitters that facilitate communication between neurons. In another application, after we eat, myosin 5 gets triggered by insulin to help move glucose from the bloodstream into the body’s cells for energy.
“If you’re healthy all of this happens properly in the background and you have no idea it’s going on,” Debold says, adding that some types of diabetes are related to the dysfunction of myosin 5.
“What we need to understand is exactly how myosin 5 works both as a single motor and as a team after it gets a signal from insulin to organize its behavior to properly deliver its cargo to the cell membrane,” he says.