Our lab studies muscle cells as a model for understanding how stem 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. We have also explored the roles of microRNAs and long non-coding RNAs 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.
Treating muscle disease by CRISPR/Cas9 genomic editing.
We are using CRISPR/Cas9 genome editing to correct muscle abnormalities associated with Duchenne muscular dystrophy. We have optimized methods for delivery and genomic editing in vivo in mice and are working toward eventual therapies for this disease. We have also generated mouse models with cardiac and muscle specific expression of Cas9 that can be used for rapid gene deletion in vivo.
Discovery and analysis of biologically active micropeptides.
We have discovered a large collection of tiny peptides expressed by muscle, heart, and the cardiovascular system. These micropeptides are encoded by small open reading frames hidden with RNAs that are misannotated as long noncoding RNAs. Micropeptides function as singular protein domains that engage larger regulatory proteins to exert powerful biological functions in cells and between tissues. We are currently exploring the functions of many micropeptides during development and disease.
We have discovered numerous cardiac and muscle specific genes of unknown function. We are currently using gain and loss of function studies in vivo and in vitro to elucidate the functions of these novel genes. Many of these novel genes appear to play critical roles in heart and muscle development and disease.
Studies of stem cells and tissue regeneration.
We are exploring the mechanisms whereby pluripotent stem cells become committed to different muscle cell lineages. We are also attempting to manipulate these decision-making processes with small molecules, microRNAs, and regulatory transcription factors. In addition, we are working to reprogram fibroblasts into cardiomyocytes as a strategy for heart regeneration.
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.
Molecular control of skeletal muscle disease
We have discovered numerous genes that control skeletal muscle formation and function. Mutations in these genes in mice have created models for understanding human muscle disease. We are currently using a variety of strategies to enhance muscle regeneration in the settings of muscle injury and diseases such as muscular dystrophy.
Metabolic signaling from muscle.
Recent studies from our group indicate that the heart and skeletal muscle exert powerful metabolic influences on the body. We are currently deciphering the gene regulatory mechanisms whereby the heart and skeletal muscle control systemic energy homeostasis and we are searching for secreted peptides (myokines) and metabolites that govern energy homeostasis.