Paul Rosenberg, M.D. is an Associate Professor of Medicine in the Department of Medicine (Cardiology).
The objective of my research program is to understand how changes in cellular calcium are decoded by a cell in order to activate signaling pathways that control gene expression, growth and differentiation, and metabolism. In particular, we are interested in Ca2+ entry pathways including store operated Ca2+ entry (SOCE)(1,2) and transient receptor potential channels (TRPC) in excitable cells (3,4,5). Major projects within the lab include: 1) understanding the mechanism by which Ca2+ contributes to muscle development, metabolism and exercise remodeling 2) defining components of the SOCE and TRPC channel complex in excitable cells, 3) understanding the function of inter-organellar Ca2+ signaling (e.g. ER, mitochondrial and nuclear).
Our work on the role of store operated Ca2+ entry has challenged the long held notion that excitable cells do not require Ca2+ entry for contractile behavior. Identification of stromal interaction molecule (STIM1) as a key regulator of SOCE in skeletal muscle has provided evidence that this pathway is critical to muscle growth and development (2). We used cultured muscle cells and genetically modified mice to show that SOCE is critical Ca2+ signaling pathway in muscle to regulate muscle gene expression (1). We have used a comprehensive assessment of muscle performance in terms of exercise and metabolism. In addition we used high speed Ca2+ imaging to study the Ca2+ signals activated by STIM1 in muscle fibers. Our results revealed a critical role linking STIM1 Ca2+ signaling to the Ca2+ events activated following tonic stimulation of muscle. We have also pursued studies to define the network of proteins that are required to carry out STIM1 dependent Ca2+ entry. Specifically we are using mammalian/yeast 2-hybrid and phage display as approaches to identify novel protein-protein interactions that involve STIM1 mediated Ca2+ signaling. These studies have shown how SOCE is in different in excitable cells that are necessary for the Ca2+ response to cardiac pacemaking and exercise remodeling. This work was supported by an NIH grant.
Our work on the electrophysiologic properties of transient receptor potential channels (TRPC) in various cell types has described how these channels contribute to stress signaling. Mutations in TRPC6 cause focal segmental glomerulosclerosis and we characterized the gain of function mutations in our collaborations with Dr. Michelle Winn’s laboratory, also a faculty member of the DMPI (4). We have also demonstrated that TRPC3/6 channels are upregulated in islet cells where Ca2+ entry by TRPC3/6 activated growth signaling during islet cell proliferation (5). Similarly we have implicated TRPC1 channels in the maladaptive signaling that occurs with pressure overload. Instead of the normal hypertrophic growth that occurs with pressure overload, TRPC1 null mice failed to manifest much disease (6,7). Thus, while these channels are quiescent in the unperturbed state, various forms of stress activate these channels. This work has been supported by the muscular dystrophy association (MDA).