The recurring theme in the lab is to discover, innovate, and lead through building ‘creative tension’ across scientific disciplines.
We develop new technologies to modulate and visualize the physical forces in living cells. To this end, the lab has the unique capability to map the cellular stress using Fourier transform traction microscopy (FTTM), to probe the material properties of living cytoskeleton using magnetic twisting cytometry (MTC), and to quantitate the molecular-level remodeling of internal structures using spontaneous nanoscale tracer motions (SNTM). These live-cell micromechanical methods are readily applicable to a wide variety of cell types and have broad research applications that are at the interface between engineering, cell biology and medicine.
We aim to understand the mechanobiology across the length scale–how cells and tissues grow, contract, move, invade and remodel. Understanding the underlying mechanisms of these fundamental biological processes can provide new approaches to tissue regeneration and therapy for diseases such as asthma, aging and cancer. Recently, we have developed a new micro-physiological system that reconstitutes 3D co-cultures of human airway smooth muscle (ASM) cells with clinically-relevant human airway epithelial cells that are fully differentiated in an air-liquid interface (Nat. Biomed. Eng. 2019). This “bronchi-chip” is fully equipped with MTC enabling the interrogation, in real-time, of the interplay between chemical and physical cues, and the heterotypic cell responses, driving asthma-like phenotype.
We explore new paradigms in sensory physiology. We have recently found ‘sensory’ G protein-coupled receptors (GPCRs) of the bitter taste receptor (TAS2R) family and the olfactory receptor (OR) family expressed on the smooth muscle of human bronchi (Nat. Med. 2010; Sci. Rep. 2016; Cell Signal 2018). TAS2Rs effectively reverse bronchoconstriction by a localized calcium flux that activates, in large part, Ca2+-activated K+ (BKCa) channels–evoking membrane hyperpolarization and smooth muscle relaxation. Human ASM cells also express multiple ORs and their obligate downstream olfaction machinery. Of note, activation of OR51E2 via its cognate ligands acetate and propionate results in marked reductions in cytoskeletal remodeling and ASM proliferation. These physiologic outcomes mediated by endogenous metabolic byproducts of the gut microbiota suggest previously unidentified “ancient” chemosensors of the gut-lung axis. The findings also give rise to the notion that ectopic expressions of sensory receptors can be exploited to discover novel disease-modifying therapeutics for asthma. We study this primordial vestige of sensory GPCR coding in the smooth muscle of human bronchi, as well as their physiologic or pathognomonic function in the development of cardiovascular diseases, aging and cancer.
