H. Lee Sweeney, Ph.D
William Maul Measey Professor in Physiology
Department: Physiology
Graduate Group Affiliations
Contact information
Richards Bldg., Rm. B400
3700 Hamilton Walk
6085
Philadelphia, PA 19104-6085
3700 Hamilton Walk
6085
Philadelphia, PA 19104-6085
Office: (215) 898-8727
Fax: (215) 573-2273
Fax: (215) 573-2273
Email:
lsweeney@mail.med.upenn.edu
lsweeney@mail.med.upenn.edu
Publications
Education:
S.B. (Biochemistry)
Massachusetts Institute of Technology, 1975.
A.M. (Physiology)
Harvard University, 1980.
Ph.D. (Physiology and Biophysics)
Harvard University, 1984.
Permanent linkS.B. (Biochemistry)
Massachusetts Institute of Technology, 1975.
A.M. (Physiology)
Harvard University, 1980.
Ph.D. (Physiology and Biophysics)
Harvard University, 1984.
Description of CVI Expertise
CVI Program Unit Administrator:Myocyte Biology / Heart Failure
CVI Research Description:
Function of contractile proteins.
Mechanisms of DCM and HCM.
Dr. Sweeney's research program addresses the molecular basis of cellular movement and force generation. His approach encompasses investigations on single molecules, single cells and whole organisms. At the level of the single molecule, the work examines the basic design and function of the molecular motor, myosin. These studies combine protein engineering with biochemical and structural analyses. At the level of isolated cells (cultured myocytes), the research program has two aspects: 1) investigation of the role of various proteins either in the generation of force, or in the transmission of force across the cell membrane, and 2) the process of assembly of the contractile apparatus. Studies at the whole animal level involve gene transfer into muscle (both germline and somatic cell). Somatic cell gene transfer (utilizing viruses) allows the assessment of acute alterations in cell structure and function following viral-driven expression of a single protein. In response to acute changes in properties, feedback pathways intrinsic and extrinsic to the muscle cell signal alterations in the muscle gene expression program that result in an adaptive response. This new approach allows critical evaluation of principles of muscle cell design as well as evaluation of possible causes of and treatments for muscle diseases. Currently, Dr. Sweeney is studying two diseases, Duchenne muscular dystrophy and hypertrophic cardiomyopathy, with this approach.
Selected Publications
Xiao, M., Reifenberger, J.G., Wells, A.L., Baldacchino, C., Chen, LQ., Ge, P., Sweeney, H.L. and Selvin, P.R.: An actin-dependent conformational change in myosin. Nat Struct Biol. 10: 402-408, 2003.Morris, C.A., Wells, A.L., Yang, Z., Chen LQ., Baldacchino, C.V. and Sweeney, H.L. : Calcium functionally uncouples the heads of myosin VI. J Biol Chem. In press 2003.
Barton-Davis, E.R., Morris, L., Musaro, A., Rosenthal, N. and Sweeney, H.L.: Muscle-specific expression of insulin-like growth factor-I counters muscle decline in mdx mice. J. Cell Biol. 157: 137-148, 2002.
Yengo, C.M., De La Cruz, E.M., Safer, D., Ostap, E.M., and Sweeney, H.L.: Kinetic characterization of the weak binding states of myosin V. Biochemistry 41: 8508-8517, 2002.
Chatterjee, S., Stewart, A.S., Bish, L.T., Jayasankar, V., Kim, E.M., Pirolli, T., Burdick, J., Woo, Y.J., Gardner, T.J., and Sweeney, H.L.: Viral gene transfer of the anti-apoptotic factor Bcl-2 protects against chronic postischemic heart failure. Circulation 106(Supp1): I-212-I-217, 2002.
Purcell, T.J., Morris, C., Spudich, J.A. and Sweeney, H.L.: Role of the lever arm in the processive stepping of myosin V. Proc. Natl. Acad. Sci. USA 99: 14159-14164, 2002.
Musaro, A., McCullagh, CK., Houghton, L., Barton-Davis, E.R., Sweeney, H.L. and Rosenthal, N.: Localized IGF-I transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature Genetics 27: 195-200, 2001.
Cordier, L., Gao, G.P., Hack, A.A., McNally, E.M., Wilson, J.M., Chirmule, N. and Sweeney, H.L.: Muscle-specific promoters may be necessary for adeno-associated virus-mediated gene transfer in the treatment of muscular dystrophies. Human Gene Therapy 12: 205-215, 2001.
Joel, P.B., Trybus, K.M. and Sweeney, H. L.: Two conserved lysines at the 50/20 kDa junction of myosin are necessary for triggering actin-activation. J. Biol. Chem. 276: 2998-3003, 2001.
Tikunov, B.A., Sweeney, H.L. and Rome, L.C.: Quantitative electrophoretic analysis of myosin heavy chains in single muscle fibers. J Appl Physiol. 90: 1927-1935, 2001.
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