Understanding cardiovascular muscle development and disease
Our lab studies muscle cells as a model for understanding how embryonic cells adopt specific fates and how programs of cell differentiation and morphogenesis are controlled during development. There are three major muscle cell types: cardiac, skeletal and smooth, which express distinct sets of genes controlled by different combinations of transcription factors and extracellular signals. We have focused on discovering novel transcription factors that control development of these muscle cell types and remodeling in response to cardiovascular and neuromuscular diseases. The processes involved in muscle development are evolutionarily ancient and conserved across diverse organisms. This conservation has enabled us to take a cross-species approach to dissect this problem by identifying myogenic regulatory genes in the fruit fly or in vertebrate embryos and to use these genes to perform gain and loss-of-function experiments in vivo and in vitro. Most recently, we have explored the roles of microRNAs in the control of muscle development and disease.Our longterm goal is to delineate the complete genetic pathways for the formation and function of each muscle cell type and to use this information to devise pharmacologic and genetic therapies for inherited and acquired muscle diseases in humans.
Our lab is made up of an international team of students and postdoctoral fellows. We also have a group of highly skilled research associates, who provide continuity to the lab and the technical infrastructure that facilitates discovery. We emphasize creativity, collaboration and camaraderie. We also have fun together and celebrate success. Our lab provides a supportive and challenging environment for students. Postdoctoral fellows are encouraged to develop their own independent projects, which they eventually take with them to serve as the foundation of their own laboratories. Many former students and postdocs from our group are emerging as the next generation of leaders in cardiovascular medicine.
Among the many projects currently being pursued in our lab are the following:
Genetic regulators of heart development.
We are using a variety of approaches to discover transcription factors that control the various steps of heart formation. The mechanisms of action of cardiogenic factors are being defined through protein-protein interaction studies, analyses of target genes, and deletion studies in mice. Transcription factors capable of reprogramming cells to cardiac fates are being investigated in cultured cells and in mouse models of heart disease.
MicroRNA control of cardiovascular development and disease.
We have discovered microRNAs that control numerous facets of cardiac biology, including myocyte growth and survival, contractility, energy metabolism, fibrosis, and angiogenesis. We are continuing to explore the roles of microRNAs in heart development and disease and are working toward the development of microRNA-based therapeutics.
Manipulation of cardiac stem cells with small molecules.
In collaboration with Jay Schneider's lab, we have discovered a collection of novel small molecules that promote cardiac gene expression in stem cells in culture as well as resident stem cells within the heart. We are dissecting the mechanisms of action of these cardiogenic molecules and using them to reprogram stem cells to cardiac fates.
Chromatin remodeling and epigenetic control of muscle development and disease.
We are exploring the roles of histone deacetylases (HDACs) and other chromatin remodeling factors in the control of muscle development and the signal-dependent regulation of muscle disease. We are also investigating the actions of HDAC inhibitors in a variety of developmental and pathologic processes.
Transcriptional control of vascular development and disease.
We are studying the transcription factors that specify smooth muscle cell fates and control the switch between smooth muscle proliferation and differentiation. A major interest is in the mechanisms of action of myocardin and myocardin-related transcription factors, which were discovered in our lab and shown to be master regulators of cardiovascular development.
Deciphering muscle gene regulatory networks in Drosophila.
The mechanisms of muscle development are evolutionarily conserved. Thus, we are performing genetic screens in Drosophila for regulators of muscle development. Genes uncovered in these screens are being mechanistically analyzed and homologs involved in mammalian muscle development are being identified and characterized.
Calcium signaling systems in muscle growth and disease.
We have identified numerous calcium signaling pathways and transcription factors that mediate muscle growth and remodeling during disease. We are pursuing a variety of strategies to manipulate these pathways and to uncover additional regulators of calcium signaling in muscle cells. One area of particular interest is the transcriptional coactivator CAMTA, which functions as a calcium-sensitive regulator of muscle gene expression.
Molecular control of skeletal muscle atrophy and ALS.
We are dissecting the signaling pathways and transcriptional mechanisms that mediate muscle atrophy. In addition, we are exploring the role of microRNAs in muscle growth, differentiation and disease. These studies include an investigation of the roles of microRNAs in amyotrophic lateral sclerosis (ALS).