Description of Research Expertise:
- Genetics & Comparative Genomics – Contractile Proteins
- Integrative Biology –Skeletal & Cardiac Muscle
- Pathobiology & Therapy – Muscular Dystrophy & Cardiomyopathy
- Vascular Approaches to Systemic Gene Delivery
Key words: Muscular Dystrophy, Integrative Biology, Myosin, Gene/Molecular Therapy, Cardiomyopathy, Comparative Genomics.
Description of Research
Most of the projects in the laboratory trace back to an underlying focus on heritable and acquired diseases affecting muscle. A recent spin-off illustrates some of the excitement and unpredictability of basic research.
As the central force-generating protein of all types of muscle, myosin can be viewed as the raison d'être for the supporting molecular machinery of muscle. An understanding of this protein, its evolutionary constraints, and its interaction with other key components of the contractile apparatus and cytoskeletal network is essential to the study of muscle disease. We have studied all of the human genes for conventional muscle myosins with the surprise finding that one of them has been mutated in a recent direct human ancestor. The temporal correlation of this mutation with the emergence of the genus Homo has provided fuel for a wide range of collaborative projects in integrative biology.
Most of the mutations implicated in the human muscular dystrophies have been mapped to genes encoding proteins involved in adhesive links between the contractile apparatus and the extracellular matrix. The myosin motors are fine, but the myocytes degenerate because the dysfunctional adhesive link disrupts cellular homeostasis as the muscles generate force. Although the mechanisms are not fully understood, gene transfer technology has been essential for dissecting the components of this system. Through this process there have recently emerged a range of interesting opportunities for translational research directed at the goal of clinical therapy. Widespread gene delivery has been a rate-limiting step in this process. The lab has made substantial progress in this area by applying novel developments in microvascular physiology and endothelial cell biology to the problem at hand. Safety studies suggest a feasible pathway to clinical therapy for muscular dystrophies, with spin-offs relevant to a spectrum of cardiac muscle and non-muscle diseases.
1. Gene Transfer for Duchenne Muscular Dystrophy
2. Molecular Evolution of Myosin Motors
3. Pathophysiology of Skeletal and Cardiomyopathy
4. Mechanisms of Morphological Change During Speciation
Kapil Gopal, M.D., Postdoctoral Fellow
Marilyn Mitchell, Research Specialist
Ben Kozyak, Pre-doctoral Student
Zhonglin Wang, M.D., Research Specialist
Xiaoqing Zheng, M.D., Visiting Scientist
Pan Pan Wang, Pre-doctoral Student
Toromanoff, Alice. Cherel, Yan. Guilbaud, Mickael. Penaud-Budloo, Magalie. Snyder, Richard O. Haskins, Mark E. Deschamps, Jack-Yves. Guigand, Lydie. Podevin, Guillaume. Arruda, Valder R. High, Katherine A. Stedman, Hansell H. Rolling, Fabienne. Anegon, Ignacio. Moullier, Philippe. Le Guiner, Caroline.: Safety and efficacy of regional intravenous (r.i.) versus intramuscular (i.m.) delivery of rAAV1 and rAAV8 to nonhuman primate skeletal muscle. Molecular Therapy: the Journal of the American Society of Gene Therapy 16 (7): 1291-9,2008.
Moore, Steven A. Shilling, Christopher J. Westra, Steven. Wall, Cheryl. Wicklund, Matthew P. Stolle, Catherine. Brown, Charlotte A. Michele, Daniel E. Piccolo, Federica. Winder, Thomas L. Stence, Aaron. Barresi, Rita. King, Nick. King, Wendy. Florence, Julaine. Campbell, Kevin P. Fenichel, Gerald M. Stedman, Hansell H. Kissel, John T. Griggs, Robert C. Pandya, Shree. Mathews, Katherine D. Pestronk, Alan. Serrano, Carmen. Darvish, Daniel. Mendell, Jerry R.: Limb-girdle muscular dystrophy in the United States. Journal of Neuropathology & Experimental Neurology 65 (10): 995-1003,2006.
Bridges, Charles R. Gopal, Kapil. Holt, David E. Yarnall, Charles. Cole, Steven. Anderson, Rochelle B. Yin, Xiaoqing. Nelson, Anthony. Kozyak, Benjamin W. Wang, Zhonglin. Lesniewski, James. Su, Leonard T. Thesier, Danielle M. Sundar, Hari. Stedman, Hansell H.: Efficient myocyte gene delivery with complete cardiac surgical isolation in situ. Journal of Thoracic & Cardiovascular Surgery 130 (5): 1364,2005.
Su, Leonard T. Gopal, Kapil. Wang, Zhonglin. Yin, Xiaoqing. Nelson, Anthony. Kozyak, Benjamin W. Burkman, James M. Mitchell, Marilyn A. Low, David W. Bridges, Charles R. Stedman, Hansell H.: Uniform scale-independent gene transfer to striated muscle after transvenular extravasation of vector. Circulation 112 (12): 1780-8,2005.
Arruda, Valder R. Stedman, Hansell H. Nichols, Timothy C. Haskins, Mark E. Nicholson, Matthew. Herzog, Roland W. Couto, Linda B. High, Katherine A.: Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model. Blood 105 (9): 3458-64,2005.
Krupnick AS, Zhu J, Nguyen T, Kreisel1 D, Balsara1 KR, Lankford EB, Clark CC, Levine S, Stedman HH, Shrager JB.: Inspiratory loading does not accelerate dystrophy in the mdx mouse diaphragm: Implications for regenerative therapy. Journal of Applied Physics 94 (2): 411-19,2003.
Kim DK, Zhu J, Kozyak BW, Burkman JM, Rubinstein NA, Lankford EB, Stedman HH, Nguyen T, Levine S, Shrager JB: Myosin heavy chain and physiological adaptation of the rat diaphragm in elastase-induced emphysema. Respiratory Research 4 : 1,2003.
Konig S, Burkman J, Fitzgerald J, Mitchell M, Su L, Stedman H.: Modular organization of phylogenetically conserved domains controlling developmental regulation of the human skeletal myosin heavy chain gene family. Journal of Biological Chemistry 277 (31): 27593-27605,2002.
Bridges CR, Burkman JM, Malekan R, Konig SK, Chen H, Yarnell CB, Gardner TJ, Stewart AS, Stecker M, Patterson T, Stedman HH.: Global cardiac-specific transgene expression using cardiopulmonary bypass with cardiac isolation. Annals of Thoracic Surgery 73 (6): 1939-46,2002.
Dejardins P, Burkman J, Shrager J, Allmond L, Stedman H.: Evolutionary implications of three novel members of the human sarcomaric myosin heavy chain gene family. Molecular Biology & Evolution 19 (4): 375-393,2002.
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