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Hansell H. Stedman, MD
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Professor of Surgery
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Attending Surgeon, Veteran Affairs Medical Center, Philadelphia, PA
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Director, Muscular Dystrophy Research Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, PA
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Department: Surgery
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Graduate Group Affiliations
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Contact information
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Perelman School of Medicine
22 University of Pennsylvania
20 709A Stellar Chance Labs
37 422 Curie Blvd.
Philadelphia, PA 19104-6069
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22 University of Pennsylvania
20 709A Stellar Chance Labs
37 422 Curie Blvd.
Philadelphia, PA 19104-6069
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Office: 215-898-1432
32 Fax: 215-573-8606
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32 Fax: 215-573-8606
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Publications
23 a
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Links
98 Search PubMed for articles
8a Cell and Molecular Biology Graduate Group
7a Department of Surgery Faculty
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98 Search PubMed for articles
8a Cell and Molecular Biology Graduate Group
7a Department of Surgery Faculty
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Education:
21 9 B.S. 22 (Chemistry and Biology) c
3e Massachusetts Institute of Technology, 1979.
21 9 M.D. c
2b Harvard University, 1984.
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3
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Permanent link21 9 B.S. 22 (Chemistry and Biology) c
3e Massachusetts Institute of Technology, 1979.
21 9 M.D. c
2b Harvard University, 1984.
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2 29
21
1e
1d
24
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43 - Genetics & Comparative Genomics – Contractile Proteins
3b - Integrative Biology –Skeletal & Cardiac Muscle
49 - Pathobiology & Therapy – Muscular Dystrophy & Cardiomyopathy
38 - Vascular Approaches to Systemic Gene Delivery
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88 Key words: Muscular Dystrophy, Integrative Biology, Myosin, Gene/Molecular Therapy, Cardiomyopathy, Comparative Genomics.
8
26 Description of Research
e3 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.
8
2bf 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.
8
429 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.
8
21 Rotation Projects
39 1. Gene Transfer for Duchenne Muscular Dystrophy
30 2. Molecular Evolution of Myosin Motors
3a 3. Pathophysiology of Skeletal and Cardiomyopathy
40 4. Mechanisms of Morphological Change During Speciation
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1e Lab personnel:
2e Kapil Gopal, M.D., Postdoctoral Fellow
2d Marilyn Mitchell, Research Specialist
28 Ben Kozyak, Pre-doctoral Student
31 Zhonglin Wang, M.D., Research Specialist
30 Xiaoqing Zheng, M.D., Visiting Scientist
29 Pan Pan Wang, Pre-doctoral Student
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19 Emergency Surgery
2d Complex Abdominal Wall Reconstructions
1a 29
27
Description of Research Expertise
2b Research Interests43 - Genetics & Comparative Genomics – Contractile Proteins
3b - Integrative Biology –Skeletal & Cardiac Muscle
49 - Pathobiology & Therapy – Muscular Dystrophy & Cardiomyopathy
38 - Vascular Approaches to Systemic Gene Delivery
8
88 Key words: Muscular Dystrophy, Integrative Biology, Myosin, Gene/Molecular Therapy, Cardiomyopathy, Comparative Genomics.
8
26 Description of Research
e3 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.
8
2bf 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.
8
429 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.
8
21 Rotation Projects
39 1. Gene Transfer for Duchenne Muscular Dystrophy
30 2. Molecular Evolution of Myosin Motors
3a 3. Pathophysiology of Skeletal and Cardiomyopathy
40 4. Mechanisms of Morphological Change During Speciation
8
1e Lab personnel:
2e Kapil Gopal, M.D., Postdoctoral Fellow
2d Marilyn Mitchell, Research Specialist
28 Ben Kozyak, Pre-doctoral Student
31 Zhonglin Wang, M.D., Research Specialist
30 Xiaoqing Zheng, M.D., Visiting Scientist
29 Pan Pan Wang, Pre-doctoral Student
65
Description of Clinical Expertise
27 General and GI Surgery19 Emergency Surgery
2d Complex Abdominal Wall Reconstructions
1a 29
23
16c Song Y, Rosenblum ST, Morales L, Petrov M, Greer C, Globerman S, Stedman HH: Suite of clinically relevant functional assays to address therapeutic efficacy and disease mechanism in the dystrophic mdx mouse. Journal of Applied Physiology 122(3): 593-602, Mar. 1 2017 Notes: Epub Dec. 8, 2016.
159 VanBelzen DJ, Malik AS, Henthorn PS, Kornegay JN, Stedman HH: Mechanism of deletion removing all dystrophin exons in a canine model for DMD implicates concerted evolution of X chromosome pseudogenes. Molecular Therapy Methods & Clinical Development 4: 62-71, Dec. 24 2016.
20e Cheever TR, Berkley D, Braun S, Brown RH, Byrne BJ, Chamberlain JS, Cwik V, Duan D, Federoff HJ, High KA, Kaspar BK, Klinger KW, Larkindale J, Lincecum J, Mavilio F, McDonald CL, McLaughlin J, Weiss McLeod B, Mendell JR, Nuckolls G, Stedman HH, Tagle DA, Vandenberghe LH, Wang H, Wernett PJ, Wilson JM, Porter JD, Gubitz AK: Perspectives on best practices for gene therapy programs. Human Gene Therapy 26(3): 127-133, Mar. 2015 Notes: Epub Mar. 3, 2015.
170 Mead AF, Petrov M, Malik AS, Mitchell MA, Childers MK, Bogan JR, Seidner G, Kornegay JN, Stedman HH: Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy. Journal of Applied Physiology 116(7): 807-815, Apr. 1 2014 Notes: Epub Jan. 9, 2014.
1b5 Fargnoli AS, Katz MG, Yarnall C, Isidro A, Petrov M, Steuerwald N, Ghosh S, Richardville KC, Hillesheim R, Williams RD, Kohlbrenner E, Stedman HH, Hajjar RJ, Bridges CR: Cardiac surgical delivery of the sarcoplasmic reticulum calcium ATPase rescues myocytes in ischemic heart failure. Annals of Thoracic Surgery 96(2): 586-595, Aug. 2013 Notes: Epub June 15, 2013.
1ab Fargnoli AS, Katz MG, Yarnall C, Sumaroka MV, Stedman H, Rabinowitz JJ, Koch WJ, Bridges CR: A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window. Journal of Cardiac Failure 17(8): 691-699, Aug. 2011 Notes: Epub June 14, 2011.
1c5 White JD, Thesier DM, Swain JB, Katz MG, Tomasulo C, Henderson A, Wang L, Yarnall C, Fargnoli A, Sumaroka M, Isidro A, Petrov M, Holt D, Nolen-Walston R, Koch WJ, Stedman HH, Rabinowitz J, Bridges CR: Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo. Gene Therapy 18(6): 546-552, June 2011 Notes: Epub Jan. 13, 2011.
13a Swain JD, Katz MG, White JD, Thesier DM, Henderson A, Stedman HH, Bridges CR: A translatable, closed recirculation system for AAV6 vector-mediated myocardial gene delivery in the large animal. Methods in Molecular Biology 709: 331-354, 2011.
ec Petrov M, Malik A, Mead A, Bridges CR, Stedman HH: Gene transfer to muscle from the isolated regional circulation. Methods in Molecular Biology 709: 277-286, 2011.
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Selected Publications
1e4 Song Y, Morales L, Malik AS, Mead AF, Greer CD, Mitchell MA, Petrov MT, Su LT, Choi ME, Rosenblum ST, Lu X, VanBelzen DJ, Krishnankutty RK, Balzer FJ, Loro E, French R, Propert KJ, Zhou S, Kozyak BW, Nghiem PP, Khurana TS, Kornegay JN, Stedman HH: Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models. Nature Medicine 25(10): 1505-1511, Oct. 2019 Notes: Epub Oct. 7, 2019.16c Song Y, Rosenblum ST, Morales L, Petrov M, Greer C, Globerman S, Stedman HH: Suite of clinically relevant functional assays to address therapeutic efficacy and disease mechanism in the dystrophic mdx mouse. Journal of Applied Physiology 122(3): 593-602, Mar. 1 2017 Notes: Epub Dec. 8, 2016.
159 VanBelzen DJ, Malik AS, Henthorn PS, Kornegay JN, Stedman HH: Mechanism of deletion removing all dystrophin exons in a canine model for DMD implicates concerted evolution of X chromosome pseudogenes. Molecular Therapy Methods & Clinical Development 4: 62-71, Dec. 24 2016.
20e Cheever TR, Berkley D, Braun S, Brown RH, Byrne BJ, Chamberlain JS, Cwik V, Duan D, Federoff HJ, High KA, Kaspar BK, Klinger KW, Larkindale J, Lincecum J, Mavilio F, McDonald CL, McLaughlin J, Weiss McLeod B, Mendell JR, Nuckolls G, Stedman HH, Tagle DA, Vandenberghe LH, Wang H, Wernett PJ, Wilson JM, Porter JD, Gubitz AK: Perspectives on best practices for gene therapy programs. Human Gene Therapy 26(3): 127-133, Mar. 2015 Notes: Epub Mar. 3, 2015.
170 Mead AF, Petrov M, Malik AS, Mitchell MA, Childers MK, Bogan JR, Seidner G, Kornegay JN, Stedman HH: Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy. Journal of Applied Physiology 116(7): 807-815, Apr. 1 2014 Notes: Epub Jan. 9, 2014.
1b5 Fargnoli AS, Katz MG, Yarnall C, Isidro A, Petrov M, Steuerwald N, Ghosh S, Richardville KC, Hillesheim R, Williams RD, Kohlbrenner E, Stedman HH, Hajjar RJ, Bridges CR: Cardiac surgical delivery of the sarcoplasmic reticulum calcium ATPase rescues myocytes in ischemic heart failure. Annals of Thoracic Surgery 96(2): 586-595, Aug. 2013 Notes: Epub June 15, 2013.
1ab Fargnoli AS, Katz MG, Yarnall C, Sumaroka MV, Stedman H, Rabinowitz JJ, Koch WJ, Bridges CR: A pharmacokinetic analysis of molecular cardiac surgery with recirculation mediated delivery of βARKct gene therapy: developing a quantitative definition of the therapeutic window. Journal of Cardiac Failure 17(8): 691-699, Aug. 2011 Notes: Epub June 14, 2011.
1c5 White JD, Thesier DM, Swain JB, Katz MG, Tomasulo C, Henderson A, Wang L, Yarnall C, Fargnoli A, Sumaroka M, Isidro A, Petrov M, Holt D, Nolen-Walston R, Koch WJ, Stedman HH, Rabinowitz J, Bridges CR: Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo. Gene Therapy 18(6): 546-552, June 2011 Notes: Epub Jan. 13, 2011.
13a Swain JD, Katz MG, White JD, Thesier DM, Henderson A, Stedman HH, Bridges CR: A translatable, closed recirculation system for AAV6 vector-mediated myocardial gene delivery in the large animal. Methods in Molecular Biology 709: 331-354, 2011.
ec Petrov M, Malik A, Mead A, Bridges CR, Stedman HH: Gene transfer to muscle from the isolated regional circulation. Methods in Molecular Biology 709: 277-286, 2011.
2c