Hansell Stedman
Associate Professor, Dept of Surgery

Gene Therapy and Vaccines Program

Address

608 Biomedical Rsch Bldg (BRB) II/III
421 Curie Boulevard
Philadelphia, PA 19104

Office tel.: 215-898-1432
Lab tel.: 215-898-1769
E-mail: hstedman@mail.med.upenn.edu

Research Interests

• 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.

Search PubMed for articles

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.

Recent Publications

Greelish JP, Su LT, Lankford EB, Burkman, JM, Chen H, Konig SK, Mercier IM, Desjardins PR, Mitchell MA, Zheng XG, Leferovich J, Gao GP, Balice-Gordon RJ, Wilson JM, Stedman HH. Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector. Nature Medicine 5(4):439-443, Apr. 1999. (Cover) (PDF link)

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. Ann. Thor. Surg. 73(6):1939-1946, June 2002.

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. J. Biol. Chem. 277(31):27593-27605, Aug. 2, 2002.

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. J. Appl. Phys. 94:411-419, 2003.

Stedman HH, Kozyak BW, Nelson A, Thesier DM, Su LT, Low DW, Bridges CR, Shrager JB, Minugh-Purvis N, & Mitchell MA. Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428:415-419, 2004 (Cover). (PDF link, 2 MB)

Lab

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