Project I. Interaction between BMP signaling and myocardin transactivity during cardiac development.
Myocardin is a transcription cofactor of serum response factor (SRF) and is specifically expressed in cardiac and smooth muscle lineages during mouse development. We have previously shown that myocardin is required for the normal development of cardiac and smooth muscles (Cell, 105, 851(2001); PNAS, 99, 14855 (2002); PNAS, 100, 7129(2003); PNAS, 100, 9366(2003)). We are currently investigating the molecular mechanisms of how myocardin functions within the transcriptional networks to control cardiovascular differentiation and growth.
BMPs (bone morphogenetic proteins) are members of the transforming growth factor ? (TGF-?) superfamily and have been shown to play important roles in the developmental events of cardiovascular system. The BMP signaling is mediated by a family of intracellular signaling producer proteins, SMADs.
We have found that the BMP signaling activates the transcriptional activity of myocardin in cardiac and smooth muscle cells. We would like to continue to study and understand how exactly such regulation occurs at the molecular level. We will apply the combination of molecular biology, biochemistry and genetic tools in our studies.
Project II. Myocardin and cardiac hypertrophy.
Cardiac hypertrophy is defined by an increase in heart size and/or myofibrillar volume without a change in myocyte number. Hypertrophic growth of the heart initially serves as a beneficial response to enhance cardiac output. However, prolonged hypertrophy inevitably progresses to dilated cardiomyopathy and heart failure, which frequently result in sudden death due to cardiac arrythymias. The causes of cardiac hypertrophy have been linked to both physiological and pathophysiological stimulation as well mechanical stresses. The molecular mechanisms of this process, however, remain unclear.
We have identified myocardin as a SAP domain transcription factor that associates with serum response factor (SRF) to potently enhance SRF-dependent transcription. Myocardin is expressed specifically in the heart and a subset of smooth muscle cells. In our preliminary studies, we found that overexpression of myocardin in cardiomyocytes induces hypertrophy. We therefore hypothesized that myocardin is one of the key transcriptional regulators during cardiac hypertrophy in response to extracellular and intrinsic hypertrophic stimuli.
The goal of this project is to determine the molecular mechanisms of how myocardin transmits hypertrophic stimuli to alter cellular responses. We will use in vitro cultured cardiomyocytes as a model system in combination with an adenoviral deliver system to address the functional role of myocardin during hypertrophy. Transgenic mouse and gene knockout techniques will also be applied to evaluate myocardin in vivo function.
