Welcome to the Breathe Lab
We study cell-cell and cell-matrix interactions in the airways to understand the fundamental mechanisms that regulate airway caliber and why they fail in diseases like asthma
Read about our projects areas below!
Overview
For many decades now, asthma has been thought of and treated as a disease of the airway smooth muscle brought about by persistent inflammation in the airways. As such, asthma is treated using a combination of anti-inflammatory drugs and bronchodilators that relax the airways smooth muscle.
However, even after inflammation is brought under control, and the asthmatic is symptom free, the patient can still experience an asthma attack in response to a small amount of an inhaled irritant like pollen or smoke. Clearly there are additional mechanisms at play in asthmatic airways that is not addressed by current therapy.
Our research focuses on pathological changes in the extracellular matrix (ECM), networks of collagen, glycosaminoglycans, proteoglycans and glycoproteins that surrounds and supports cells in tissue and their role in regulating airway constriction in healthy and asthmatic subjects.
Our Projects
Computational Modeling
We developed a computational model of a cell pair on a rectangular pattern in which subcellular force exertion mechanisms are taken into account, specifically adhesion complex maturation and stress fiber strengthening.
The model provides viable molecular explanations for decoupling: mechanosensing mechanisms are responsible for competition between different fiber-adhesion configurations present in the cell pair.
The point at which increasing substrate stiffness becomes as high as that of the cell-cell interface is the tipping point at which configurations that favor cell-substrate adhesion dominate over those favoring cell-cell adhesion.
Smooth Muscle Mechanics
Smooth muscle cells constrict in response to a wide range of chemical stimuli. The mechanisms by which these cells sense contractile stimuli and generate a proportionate force were thought to be intrinsic to each smooth muscle cell.
We discovered that contrary to current dogma, human smooth muscle cells sense agonist concentrations by communicating with each other by frequency modulating intercellular Ca2+ waves.
The stiffening of the underlying ECM can cause a break down in this intercellular communication resulting in healthy cells erroneously sensing a small dose of irritant (like pollen) as a high dose and generating excessive force, as seen in asthma
Image on the left shows human smooth muscle cells loaded with a fluorescent indicator of cytosolic Ca2+ concentration
Cell-matrix Interactions
For an airway or a blood vessel to narrow, there must be a connected path that links the smooth muscle (SM) cells with each other, and transmits forces around the organ, causing it to constrict.
Currently, we know very little about the mechanisms that regulate force transmission pathways in a multicellular SM ensemble. We show that changes in the mechanics of its external environment triggers a change in connectivity in cells.
On soft/healthy ECM, cells transmit their force through cadherin- based cell-cell connections. But on stiff/diseased environments, cells switch their connectivity to integrin based focal adhesions. The change in connectivity can also significantly change the overall contractile strength of the ensemble. Excessive contraction of airways and blood vessels can therefore emerge as a result of change in connectivity among SM cells driven by ECM.