Senior Associate Dean for Basic Research, Biotechnology and Graduate Studies, School of Medicine and Public Health
Ph.D., Univ of Vermont
Postdoctoral Research, Boston Biomedical Research Institute
My laboratory studies contractile processes in heart and skeletal muscles and alterations in contraction in diseases such as heart failure. A primary focus of our research is the set of mechanisms by which calcium, various physical factors and signal transduction pathways regulate myocardial contraction.
We use a range of investigative approaches including biophysics, biochemistry and molecular biology in our studies of these mechanisms. Most of our experiments involve measurements of contractile properties of single muscle cells in response to alteration in contractile protein composition, which is done by biochemical exchange, gene knock-outs, and expression of proteins on a null background. In this way, we are able to assess the roles of specific proteins in regulation and determine the roles of specific domains in protein function.
Another focus of our research is the molecular mechanisms that determine the work capabilities of myosin molecules, which is essentially a study of the kinetics of nucleotide turnover by myosin. Our interest in this problem is stimulated by the observation that different myosin isoforms have widely varying work rates, which gives rise to variable work rates among the muscles of the body. Even the same myosin isoform expressed in different species can have dramatically different turnover kinetics, and work rates can be dramatically slowed in disease states such as heart failure and ischemic heart disease.
Our investigations of this mechanism feature systematic mutation of myosin molecules, expression in a baculovirus/insect cell system, and measurement of function using an in vitro motility assay system. Studies such as these are probing the most fundamental processes of the actomyosin ATPase, and results will presumably also have implications for our understanding of altered contraction in diseased heart muscle.
In this regard, the laboratory is presently engaged in extensive studies of the basis for contractile dysfunction in animal models of heart failure (CREB-A133 dominant-negative mouse) and myocardial stunning.
Background: a single mouse myocyte is anchored to two pins connected to a force transducer and length control device in order to measure force and kinetics of activation.