Our lab is interested in understanding cytoskeletal molecular motors and their role in mechanobiology. We have several projects that we are currently pursuing:
Mechanobiology of cardiac contraction:
The heart is a finely tuned machine that fills with blood during relaxation and then contracts, generating force and power to deliver blood to the rest of the body. Moreover, the heart senses its mechanical environment and adjust its power output in response to various stimuli. Impairment of force generation and/or force sensing by the heart can lead to several heart conditions. We have developed tools that enable us to reconstitute aspects of cardiac contraction from the level of single molecules to the level of human engineered heart tissues, and we are examining how mechanical cues affect cardiac contractility.
Familial cardiomyopathies are found in up to 1 in every 500 people, and these conditions are the leading cause of sudden cardiac death in young people. In patients with pediatric onset disease, these conditions are especially devastating. Patients with these diseases show alterations in the structural and mechanical properties of the myocardium. Human genetic studies have shown that the most common cause of familial cardiomyopathies is mutation of the proteins involved in generating and regulating force and power output in the heart; however, it is not well understood how changes at the molecular scale lead to alterations in cardiac contractility at the cellular and tissue levels. We have developed molecular, cellular, and tissue-scale models of these diseases, and we are using computational modeling to link these various scales. The understanding gained from our studies may facilitate the design of targeted therapies for cardiomyopathies.
Our studies require tools for studying contractility across multiple levels of organization. We are actively developing tools that enable us to model heart contractility at the molecular, cellular, and tissue levels. For our molecular studies, we have developed an optical trapping system with force feedback to study the contractility of single motor proteins. For our cellular studies, we use CRISPR/Cas9 to introduce disease-causing mutations into human stem cells, and then differentiate these stem cells into cardiomyocytes. We use engineering techniques to study the contractility of single cells and to mimic the electrical and mechanical environments of the heart. For our tissue level studies, we are generating human engineered heart tissues in microelectromechanical devices. Importantly, these tools will give us an unprecedented understanding of how the heart generates force and power in both health and disease.