CAREER: Elucidating the Role of Collective Cell-Matrix Interactions in the Mechanobiology of Airway Narrowing

This Faculty Early Career Development (CAREER) award aims to reveal how physical forces enable the airway smooth muscle and the surrounding tissue to work together to detect inhaled irritants and regulate the constriction of airways. Everyday life exposes us to many inhaled irritants. These can cause our airways to constrict, making it difficult for us to breathe.

Although it is known that airways constrict due to the force generated by the airway smooth muscle, how the muscle detects the inhaled irritant and generates a proportionate force is not well understood. The basic scientific knowledge gained in this work can lead to new therapies. For example, therapies that target the airway's extracellular components may offer lasting relief for the millions of people worldwide who struggle with breathing difficulties.

In parallel with the laboratory research, this award will engage students and pique their curiosity about the world around them. Specifically, high school students from underrepresented minority groups will have opportunities to perform laboratory research, receive mentoring support, and coaching for college admission. Online educational modules will make innovations in teaching science and engineering accessible for K-12 educators in remote, rural areas.

Together, this work will inspire a new generation of bioengineers who are driven to understand the fundamental mechanisms that maintain human health and create a better world through science and technology.

This project investigates the mechanisms that underlie a newly discovered phenomenon in the smooth muscle where cells can work together to sense contractile stimuli as a collective. In collective agonist sensing, smooth muscle cells communicate with each other, using their force to modulate the frequency of intercellular calcium waves. By communicating with each other, the ensemble can completely change how each cell perceives contractile stimulus and the overall force it generates.

The mechanisms that underlie this collective behavior of the smooth muscle and its implications for airway narrowing are currently unknown. The research goal of this is to elucidate the mechanisms that regulate collective agonist sensing and to understand the impact of the underlying mechanobiological interactions in regulating airway caliber. Specifically, this will test a hypothesis that collective agonist sensing by a multicellular smooth muscle cell ensemble relies on its ability to dynamically change the connectivity among individual cells in a force-dependent manner.

To this end, we have set up the following aims: 1) Test the hypothesis that mechanical signaling between smooth muscle cells regulates agonist sensing in SMC ensembles. 2) Quantify the impact of deep breaths on the force response of smooth muscle cell ensembles. 3) Establish the role of mechanobiology in regulating airway narrowing in lung tissue. Upon successful completion, we will provide the community with a detailed description of a hitherto unknown control system that regulates airway caliber.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.