Our research program focuses on calcium-dependent signaling pathways and excitation transcription coupling in striated muscle. Major projects include:
- The spatial and temporal properties of calcium signals that activate the calcium-dependent transcription
- Novel calcium-signaling molecules
- Calcium-signaling pathways active during striated muscle physiology and development
Our research seeks to understand how changes in calcium are decoded by a cell to activate signaling pathways that regulate transcription. We have recently demonstrated that specific calcium signals from transient receptor potential (TRPC) channels regulate gene expression in striated muscle through the calcineurin signaling pathway.
Moreover, adaptive signals from TRPC channels establish a form of cellular memory of calcium signaling that is unregulated to alter the gain calcineurin/NFAT signaling for subsequent stimuli. Not surprisingly, the promoter of TRPC3 is activated by NFAT signaling in an autoregulatory loop. We have now embarked on studies to identify additional calcium memory proteins including homer proteins and calcium signaling scaffolds to concentrate signaling molecules in the cell. We are also focused on the calcium sensor stromal interaction molecule (STIM1) in striated muscle.
A second focus of our research seeks to understand mechanisms involved in regulation of TRPC channel activity. We have shown that at least two factors interact independently to drive TRPC channel activity: Surface expression of the channel and transcriptional regulation. In collaboration with Michelle Winn, MD, of the Center for Human Genetics, we have characterized the properties of mutant TRPC6 channels that were identified in a family with focal segmental glomerulosclerosis. We believe that these studies will lead to enhanced understanding of the specificity of various calcium pools and how they regulate distinct calcium-mediated processes, such as contraction and gene expression.
- Stiber J, Tabetei N, Hawkins AF, Hawke T, Williams RS, Rosenberg P. Homer modulates NFAT dependent signaling during skeletal muscle development.Developmental Biology, 2005 Nov 15;287(2):213-24
- Winn M, Conlon P, Lynn K, Farrington K, Kwan Q, Ebersville S, Burchette JL, Graham FL, Peace TR, Quarle LD, Pericak-Vance M, Howell DN, Vance JM, Rosenberg P. A Mutation in the Transient Receptor Potential Cation Channel 6 (TRPC6) Causes Familial Focal Segmental Glomerulosclerosis.Science, Jun 17;308(5729):1801-4. This work describes a mutation in TRPC6 gene in a family with FSGS. This is the first evidence linking TRPC channels to a human disease. This paper was chosen for Faculty 1000 and was featured in several reviews in Nature and Science STKE.
- Rosenberg P, Hawkins AF, Stiber J, Bassel-Duby R, Yan Z, Williams RS. TRPC3 confers cellularmemory of recent neurostimulation. Proc Nat Acad Sci USA. 2004June 15; 101(25) 9387-9392. In the report, we provide evidence that TRPC3 is activated as an autoregulatory loop to enhance NFAT signaling in endurance trained muscle. This manuscript was chosen for Faculty 1000.
- Rosenberg P. Mitochondrial Dysfunction and Cardiovascular Disease.Mitochondrion (4) 2004, 624-628
- Williams RS, Rosenberg PB. Calcium-dependent gene regulation in myocyte hypertrophy and remodeling. ColdSpring Harb Symp Quant Biol. 2002; 339-345.
- Wu H, Rothermel B, Rosenberg P, Naya FJ, Shelton JM, Hutcheson KA, DiMaio JM, Olson EN, Bassel-Duby R, Williams RS. Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway.EMBO J. 2001; 20:6414-6423
- Akimoto T, Pohnert S, Li P, Zhang M, Gumbs C, Rosenberg P, Williams RS, Yan Z. Exercise stimulates PGC-1alpha transcription in skeletal muscle through activation of the p38MAPK pathway. J Biol Chem. 2005May 20; 280(20) 19587. In this work we characterize the promoter of PGC-1 and show that PGC-1 regulation is activated by the p38 stress activated pathway in the skeletal muscle of endurance-trained mice.
- Wu H, Stiber J, Rosenberg P, Meissner G, Eu J. Ryanodine receptors in muscarinic receptor-mediated Bronchoconstriction. J Biol Chem (2005 Jul 15;280(28):26287-94
- Shelton JM, Martin CM, Ward CC, Richardson JA, Williams RS, Garry DJ, Rosenberg P. Calcineurin and NFAT signaling during mouse development.Mechanism of Development Accepted August 2006.
- Konhilas JP, Watson P, Maass A, Boucek DM, Horn T, Stauffer B, Luckey SW, Rosenberg P, Leinwand LA. Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy. Circulation Research. 2006 Mar 3;98(4):540-8
Jonathan Stiber, MD
Paul Rosenberg, MD
Office: Duke Department of Medicine, Durham, NC, 27710
Campus mail: Box 103032, Durham, NC, 27710