Vice Dean, Innovation and Development
Co-Director, Sarver Heart Center
Director, Molecular Cardiovascular Research Program
Professor, Cellular and Molecular Medicine
Professor, Molecular and Cellular Biology
Professor, BIO5 Institute
- Roswell Park Cancer Institute, Buffalo, New York, 1992 (Ph.D.)
- The Scripps Research Institute, La Jolla, California 1992-1996(Postdoctoral Research)
Identification of the molecular components and signaling mechanisms that regulate cytoskeletal protein interactions during striated muscle development.
The research in my laboratory is focused on identifying the components and molecular mechanisms regulating actin filament length, assembly and organization. Control of actin filament length and dynamics is important for cell motility and architecture and is regulated in part by capping proteins that block elongation and depolymerization at both the fast-growing (barbed) and slow-growing (pointed) ends. To identify the role of various actin-binding proteins, including tropomodulin, the only recognized actin filament pointed end capping protein, primary cultures of chick cardiac myocytes and skeletal myogenic cells are being used as model systems. Striated muscle is an ideal model system for these studies due to the precise organization and polarity of cytoskeletal components within repeating sarcomeric units (for example, the ~1 mm long actin filaments are easily resolved by light microscopy). Using this system we can combine morphological and biochemical approaches with direct tests of physiological function.
Recently, we demonstrated that pointed end capping by tropomodulin is required to maintain actin filament length in vivo and that this is essential for contractile function. In addition, our results indicate that separate domains of tropomodulin subserve different physiological properties. We are presently using two approaches to identify further the in vivo functional properties of tropomodulin. These include: 1) microinjection of domain-specific, function-blocking antibodies and 2) overexpression of truncated or mutant tropomodulins by cDNA transfection or by microinjection of recombinant tropomodulin fragments.
In the future, to complement the studies described above, the role of tropomodulin and other actin regulatory proteins will be studied in motile cells: that is, in cells where actin filament lengths are maintained at different lengths.
Gregorio CC, Perry CN, McElhinny AS. Functional properties of the titin/connectin-associated proteins, the muscle-specific RING finger proteins (MURFs), in striated muscle.
J Muscle Res Cell Motil. 26(6-8):389-400, 2005.
McElhinny AS, Schwach C, Valichnac M, Mount-Patrick S, Gregorio CC. Nebulin regulates the assembly and lengths of the thin filaments in striated muscle. J Cell Biol. 170(6):947-57, 2005.
Ono Y, Schwach C, Antin PB, Gregorio CC. Disruption in the tropomodulin1 (Tmod1) gene compromises cardiomyocyte development in murine embryonic stem cells by arresting myofibril maturation. Dev Biol. 282(2):336-48, 2005.
McElhinny AS, Perry CN, Witt CC, Labeit S, Gregorio CC. Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate filament and sarcomeric M-line maintenance in striated muscle development. J Cell Sci. 117(Pt 15):3175-88, 2004.