Research

The goal of the HAMM lab’s research is to understand the molecular and cellular mechanisms that regulate muscle contraction, using a variety of molecular biology, genetic and biomechanical approaches. This information is used to develop complex computational models of contraction at the protein and sarcomere level. Models contain spatial (geometry) and kinetic information, and provide clues to the mechanistic processes that are difficult to obtain from experimental measurements. A more recent interest in our group is to apply knowledge gained from these experiments to design therapies to improve the performance of diseased cardiac and skeletal muscle. Many research projects are done in collaboration with other laboratories at the University of Washington, at other institutions across the US, and in Italy.

Molecular Mechanisms of Striated Muscle Contraction

The HAMM lab uses protein engineering to design contractile regulatory proteins, which can be exchanged for the native proteins in cardiac and skeletal muscle cells, to study how they affect contractile performance. Measurements of actin-myosin interaction, the calcium binding dynamics of regulatory proteins, and the kinetic relationship between these two processes are assessed using protein biochemistry and biomechanics at the level of isolated proteins, single myofibrils, whole cells, tissue, and whole organ. Some of these projects are done in collaboration with the Pogessi lab in Florence, Italy.

Computational Models of Protein and Muscle Sarcomere Dynamics

The HAMM lab collaborates with the Daniel lab to develop, test, and utilize computational models of varying complexity to understand the sarcomere protein interactions involved in cardiac and skeletal muscle contraction. The models are developed hand-in-hand with experimental data collected in the HAMM lab. Models are currently run on a computer node with 18 parallel processors, with plans to upgrade to a larger system. Chemo-mechanical models of actin-myosin ‘crossbridge’ aid in understanding the conversion of ATP hydrolysis to muscle work, and how this is regulated during calcium activation. We have recently developed the first spatially explicit, stochastic kinetic model of a 3-dimensional myofilament half-sarcomere, which includes the kinetics of thin filament activation coupled with crossbridge cycling, and demonstrates the importance of sarcomere lattice geometry in crossbridge recruitment. Further development of the model will investigate the Frank-Starling Law of the heart and the reduced work capacity of cardiac and skeletal muscle with pathological conditions.

Cardiac Repair and Therapeutics

In collaboration with the Murry and Ratner labs (and others), we are working on methods to improve cardiac function following myocardial infarct (heart attack). One experimental approach involves cell transplantation of cardiomyocytes and engineered tissue constructs into damaged regions and tissue engineering. Ongoing experiments access cell survivability and contractile properties, effects on non-infarct regions and methods to improve the incorporation of transplanted cells into the host tissue. An additional approach we have recently begun is to use adenoviral transfection strategies to re-engineer sarcomere proteins and contractile substrate conditions for improved cardiac function.