UC Riverside physicist Thomas Kuhlman has received a $400,000 National Science Foundation grant to investigate whether cells communicate through the timing of protein activity, a hypothesis that could reshape scientists’ understanding of gene regulation.
The research will focus on the MAPK signaling pathway, which cells rely on to activate genes needed to respond to stresses such as heat, infection, ultraviolet light, and nutrient changes. Scientists have long known the pathway controls many stress responses, but how cells select the correct genetic program has remained unclear.
“Every day, your cells encounter an essentially infinite variety of different kinds of stresses in the environment,” said Kuhlman, an associate professor of physics and astronomy and the three-year grant’s principal investigator. “The question is simple to understand: How is it possible that this one single enzyme can correctly regulate hundreds of different possible responses without activating the wrong ones or multiple responses at once?”
Kuhlman will investigate whether cells rely on the timing of protein activity — not simply whether proteins are on or off — to determine how they respond to stress. His team recently found evidence that p38 MAPK communicates through repeating waves of activity rather than acting as a simple on-off switch, a mechanism the researchers call biochemical resonance. Like radios tuned to different frequencies, cells may use these oscillations to trigger specific genetic responses.
The project will test whether biochemical resonance extends beyond p38 to other MAPK proteins. The researchers will develop fluorescent biosensors to watch these proteins switch on and off inside living cells in real time.
Kuhlman explained that if biochemical resonance proves to be a general feature of cell signaling, it could reveal a new principle governing how cells process information and regulate genes, with long-term implications for designing more precise therapies.
The project will also examine whether disruptions in biochemical resonance contribute to diseases linked to MAPK signaling, including Alzheimer’s disease, ALS, and inflammatory disorders.
Kuhlman believes the research project’s greatest significance may lie in expanding scientists’ understanding of how cells function.
“Understanding something new at such a fundamental level has some broad possibilities,” he said. “This work could give us new basic insights into how genes are regulated and entirely new mechanisms to control and alter gene expression in human cells.”