This proposal describes a five year training program for an academic career in molecular cardiology. The principal investigator has completed clinical training in internal medicine and cardiology at Duke University Medical Center and has been named to the faculty of the Department of Medicine of Duke University with the title of Associate of Medicine. The principal investigator has spent the last two years in the laboratory of R. Sanders Williams obtaining research training in molecular biology and cellular physiology. The sponsor, Dr. R. Sanders Williams has successfully mentored numerous graduate students, post-doctoral fellows, and cardiologists who have gone on to careers in academic medicine. The Division of Cardiology at Duke University has also demonstrated a strong commitment to the development of academic careers of young faculty. Calcineurin, a calcium regulated serine threonine phosphatase, modulates profiles of gene expression in skeletal and cardiac muscle associated with fiber type differentiation and cardiac hypertrophy. Homer proteins are a family of scaffolding proteins which play a critical role in calcium signaling by mediating the interaction between cell surface proteins and receptors on the SR/ER such as the IP3 and ryanodine receptors. The goal of this project is to determine the role of Homer proteins in regulating calcineurin signaling and its effects on muscle remodeling and cardiac hypertrophy.
The Specific Aims are as follows: 1) To characterize the spatial and temporal patterns of expression of Homer isoforms in striated muscle during embryonic development and in response to physiologic stimuli. 2) To determine the role of Homer proteins in myotube development and calcineurin signaling in a tissue culture model. Here we will assess our hypothesis that Homer isoforms influence myotube development, calcium signaling, and activation of the calcineurin/NFAT signaling pathway. 3) To determine the effect of both overexpression and targeted disruption of Homer isoforms on cardiac and skeletal muscle function in mouse models. Here we will use a gain of function/loss of function strategy to determine the role of Homer proteins in vivo in the remodeling events associated with fiber-type differentiation and cardiac hypertrophy.
| Nepliouev, Igor; Zhang, Zhu-Shan; Stiber, Jonathan A (2011) Effect of oxidative stress on homer scaffolding proteins. PLoS One 6:e26128 |
| Stiber, Jonathan A; Seth, Malini; Rosenberg, Paul B (2009) Mechanosensitive channels in striated muscle and the cardiovascular system: not quite a stretch anymore. J Cardiovasc Pharmacol 54:116-22 |
| Stiber, Jonathan; Hawkins, April; Zhang, Zhu-Shan et al. (2008) STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat Cell Biol 10:688-97 |
| Stiber, Jonathan A; Zhang, Zhu-Shan; Burch, Jarrett et al. (2008) Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity. Mol Cell Biol 28:2637-47 |
| Stiber, Jonathan A; Tabatabaei, Niloufar; Hawkins, April F et al. (2005) Homer modulates NFAT-dependent signaling during muscle differentiation. Dev Biol 287:213-24 |
