June 18, 2024
On the front lines of exposure to the rest of the world, the body’s airways are confronted by dangers ranging from air pollution to allergens to mis-swallowed coffee. To cope, they have defensive reflexes, such as coughing, and repair responses that marshal stem cells to remodel damaged tissue. But in many diseases, such as asthma and chronic obstructive pulmonary disorder (COPD), the lungs’ remodeling responses go awry causing serious and even fatal impairments to breathing.
While such diseases and their impact are well known, what is much less clear is how these remodeling responses are triggered, coordinated and resolved. With a new Pew Scholar in the Biomedical Sciences Award from the Pew Charitable Trusts, Sara Prescott, assistant professor in the Department of Biology and The Picower Institute for Learning and Memory at MIT, is set to test the hypothesis that various types of neurons in the airways are central players in both healthy and pathological remodeling.
“In barrier tissues such as our lungs, neurons serve as sentinels where they’re detecting the earliest signs of airway damage and sending that information back to the brain to trigger protective reflexes,” Prescott said. “But these neurons are also present at the right places and sensing the same irritants and hazards that cause remodeling. It seems like they are strategically placed in such a way that they’re poised to communicate the insult to the tissue. And yet because it has been historically very challenging to selectively access these neurons experimentally, people have largely ignored their role in these diseases. They’re often just thought of as bystanders and we want to challenge that assumption.”
Prescott has been studying and characterizing airway neurons stemming from the vagus nerve for years. She has also begun investigating other neuron types, like sympathetic innervation of the airways. With the Pew award’s support of $300,000 over four years, Prescott and her lab members plan to apply that knowledge and new techniques her lab has developed to conduct experiments with mice that will test the role of neurons in coordinating airway stem cell remodeling. These will include selectively stimulating different neuron types that innervate the airway to see if that drives different remodeling responses. The lab expects to also test whether taking these neurons offline will hinder remodeling mechanisms in animals exposed to respiratory insults. In a third set of experiments, Prescott’s team intends to put airway stem cells in a dish and expose them to various factors emitted by airway neurons to see which ones appear to stimulate stem cell remodeling responses.
Understanding whether and how specific types of neurons guide the lung’s remodeling response could be a critical step in discovering new therapeutic strategies to address remodeling diseases, which don’t have any cures, Prescott said.
“Our hope is to use these insights to build therapeutics that could halt or reverse airway scarring, or other features of remodeling, in the future,” she said.
Prescott added that she is honored to have Pew’s support for the project, which might have been difficult to fund via traditional means.
“I’m incredibly grateful for this opportunity,” Prescott said. “It can be quite challenging to get funding for projects when they are in their early development phase, especially projects that sit at the intersection of two disciplines like neuroscience and stem cell biology. The funding that’s coming from the Pew Charitable Trusts is allowing us to pursue questions that we think are important and potentially transformative.”
