The main research interest of our laboratory group is to examine the molecular mechanisms regulating force transmission in smooth muscle that play a role in chronic airways diseases such as asthma and COPD. In smooth muscle, force is generated by classical intracellular actin-myosin cross-bridging, and transmitted to a network of tethering via cell-matrix and cell-cell junctional proteins. Our lab is interested in how force is efficiently translated from individual cells throughout the airways by actin-binding proteins tethered to transmembrane proteins such as integrins and cadherins.

Recently, we have determined that ligation of specific transmembrane integrins and cadherins have functional effects on force generation that are independent of changes in actin-myosin cross-bridging. Current studies in the lab are directed at further understanding the relative contribution and interaction between cellular tethering pathways in transmitting force on cellular, tissue, and in vivo scale in states of health and disease. Our laboratory utilizes transgenic and knockout approaches, ex vivo an in vivo contraction assays, as well as advanced imaging techniques to visualize and quantify force transmission. In addition to these ongoing studies, we also collaborate with members of the DeGrado lab to advance the design, screening, and validation of more potent small molecule inhibitors of novel targets we have identified.

Current Projects

Integrin Mediated Smooth Muscle Force Transmission

Integins are a class of adhesion proteins that bind the cell to specific proteins in the surrounding extracellular matrix. Our prior work has shown that these extracellular bonds are neccessary to trasmit force from actin-myosin crossbriging in the muscle to the surrounding tissue. We are broadly interested in how pro-inflammatory cytokines modulate these pathways, and how they can be manipulated therapeutically.

Cadherin Mediated Smooth Muscle Force Transmission

Cadherins are calcium dependent adhesion proteins that are an important part of adherens junctions between individual cells. We have shown that disruption of select cadherin-cadherin interactions can have important effects on force transmission in airway smooth muscle. We are interested in exploring how these proteins regulate force transmission, how they cross-talk with integrin-mediated tethering pathways, and how they can be therapeutically leveraged.

Novel Drug Discovery

Having identified key target proteins involved in force transmission in smooth muscle, we are interested in collaborative efforts to develop more potent and specific small molecule inhibitors for use in diseases including but not limited to chronic airways diseases. We have a long-standing collaboration with the DeGrado lab to design and validate novel small molecule inhibitors through in vitro, ex vivo, and in vivo platforms. We are also interested in continued collaborative efforts to apply our small molecule inhibitors to diseases outside of the airways where integrins or cadheirns may play an important role.