David Wieczorek

David F Wieczorek

Professor

Cardiovascular Rsrch Cntr

2939

COM Mol Gen Wieczorek Lab - 0524

2939 Cardiovascular Center
231 Albert Sabin Way
Cincinnati, Ohio 45267-0524

Professional Summary

The principal focus of Dr. Wieczorek's lab addresses two fundamental areas of muscle biology: (1) the functional significance for the production of different tropomyosin isoforms in vertebrates; and (2) the structural, physiological, and molecular effects on the heart following overexpression or ablation of normal or disease-associated tropomyosins. Using recombinant DNA technology, coupled with manipulations of the mouse genome, we address the developmental and physiological significance of these tropomyosin isoforms. We conduct these investigations by generating transgenic mice which overexpress a specific tropomyosin isoform (or which have had a tropomyosin isoform removed from their genome) and conduct morphological and physiological measurements on their hearts. In addition to these exciting studies, we also investigate how specific tropomyosin mutations which are associated with human diseases affect muscle assembly and function, and thus provide animal models for understanding diseases associated with the cardiovascular and skeletal muscle systems.

Education

B.A., University of California, Berkeley 1975

Ph.D., Rutgers University 1981

M.S., Rutgers University New Brunswick, NJ, 1976 (Human Genetics)

Research and Practice Interests

Our research interests lie in the understanding of muscle contractile proteins associated with both normal and diseased function.   More specifically, we focus on tropomyosin, a sarcomeric thin filament protein found in skeletal and cardiac muscle. Our research addresses the physiological significance of tropomyosin (Tm) isoforms with respect to sarcomeric function and their role in cardiac disease.  Our approach utilizes transgenic and knockout mice to determine how the cardiac sarcomere and the heart undergo remodeling in response to different Tm isoforms and genetically-defined mutations that correspond to human hypertrophic and dilated cardiomyopathies.  Our recent work examines how Tm phosphorylation influences sarcomeric performance and cardiac function, along with the molecular pathways that are activated by this process.

Research Support

Grant: #2005-01482-01-00 Investigators:Wieczorek, David 08-22-2005 -08-21-2008 Philip Morris USA Nicotine and Genetically Linked Hypertrophy, Hypertrophic, Hypertrophic Cardiomyopathy Role:PI $156,560.00 Closed Level:Industry

Grant: #R01-HL-071952 Investigators:Wieczorek, David 08-01-2003 -06-30-2008 National Heart, Lung and Blood Institute Mechanisms of Tropomyosin Induced Hypertrophy Role:PI $2,033,172.00 Closed Level:Federal

Grant: #R01-HL-079032 Investigators:Wieczorek, David 06-01-2005 -04-30-2009 National Heart, Lung and Blood Institute Control of Cardiac Function by Calcium and Myofilaments Role:PI $153,750.00 Closed Level:Federal

Grant: #5-R01-HL-54912-05-A0-S0-E0 Investigators:Wieczorek, David 05-01-1996 -04-30-2002 National Heart, Lung and Blood Institute Functional Analysis of Tropomyosin in the Heart Role:PI $1,243,728.00 Closed Level:Federal

Grant: #R01 HL081680 Investigators:Wieczorek, David 07-20-2007 -06-30-2012 National Heart, Lung and Blood Institute The Regulation of Sarcomeric Function by Tropomyosin Role:PI $1,571,720.00 Closed Level:Federal

Publications

Peer Reviewed Publications

Schulz, Emily M; Correll, Richard N; Sheikh, Hajer N; Lofrano-Alves, Marcos S; Engel, Patti L; Newman, Gilbert; Schultz, Jo El J; Molkentin, Jeffery D; Wolska, Beata M; Solaro, R John; Wieczorek, David F (2012. )Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy.The Journal of biological chemistry, ,287 ,44478-44489

Al Moamen, Nabeel J; Prasad, Vikram; Bodi, Ilona; Miller, Marian L; Neiman, Michelle L; Lasko, Valerie M; Alper, Seth L; Wieczorek, David F; Lorenz, John N; Shull, Gary E (2011. )Loss of the AE3 anion exchanger in a hypertrophic cardiomyopathy model causes rapid decompensation and heart failure.Journal of molecular and cellular cardiology, ,50 (1 ),137-46

Jagatheesan, Ganapathy; Rajan, Sudarsan; Ahmed, Rafeeq P H; Petrashevskaya, Natalia; Boivin, Greg; Arteaga, Grace M; Tae, Hyun-Jin; Liggett, Stephen B; Solaro, R John; Wieczorek, David F (2010. )Striated muscle tropomyosin isoforms differentially regulate cardiac performance and myofilament calcium sensitivity.Journal of muscle research and cell motility, ,31 (3 ),227-39

Jagatheesan, Ganapathy; Rajan, Sudarsan; Wieczorek, David F (2010. )Investigations into tropomyosin function using mouse models.Journal of molecular and cellular cardiology, ,48 (5 ),893-8

Rajan, Sudarsan; Jagatheesan, Ganapathy; Karam, Chehade N; Alves, Marco L; Bodi, Ilona; Schwartz, Arnold; Bulcao, Christian F; D'Souza, Karen M; Akhter, Shahab A; Boivin, Greg P; Dube, Dipak K; Petrashevskaya, Natalia; Herr, Andrew B; Hullin, Roger; Liggett, Stephen B; Wolska, Beata M; Solaro, R John; Wieczorek, David F (2010. )Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.Circulation, ,121 (3 ),410-8

Jagatheesan, Ganapathy; Rajan, Sudarsan; Schulz, Emily M; Ahmed, Rafeeq P H; Petrashevskaya, Natalia; Schwartz, Arnold; Boivin, Greg P; Arteaga, Grace M; Wang, Tao; Wang, Yi-Gang; Ashraf, Muhammad; Liggett, Stephen B; Lorenz, John; Solaro, R John; Wieczorek, David F (2009. )An internal domain of beta-tropomyosin increases myofilament Ca(2+) sensitivity.American journal of physiology. Heart and circulatory physiology, ,297 (1 ),H181-90

Wieczorek, David F; Jagatheesan, Ganapathy; Rajan, Sudarsan (2008. )The role of tropomyosin in heart disease. Advances in experimental medicine and biology, ,644 ,132-42

Jagatheesan, Ganapathy; Rajan, Sudarsan; Petrashevskaya, Natalia; Schwartz, Arnold; Boivin, Greg; Arteaga, Grace M; Solaro, R John; Liggett, Stephen B; Wieczorek, David F (2007. )Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis.American journal of physiology. Heart and circulatory physiology, ,293 (2 ),H949-58

Rajan, Sudarsan; Ahmed, Rafeeq P H; Jagatheesan, Ganapathy; Petrashevskaya, Natalia; Boivin, Greg P; Urboniene, Dalia; Arteaga, Grace M; Wolska, Beata M; Solaro, R John; Liggett, Stephen B; Wieczorek, David F (2007. )Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity.Circulation research, ,101 (2 ),205-14

Rajan, Sudarsan; Williams, Sarah S; Jagatheesan, Ganapathy; Ahmed, Rafeeq P H; Fuller-Bicer, Geraldine; Schwartz, Arnold; Aronow, Bruce J; Wieczorek, David F (2006. )Microarray analysis of gene expression during early stages of mild and severe cardiac hypertrophy.Physiological genomics, ,27 (3 ),309-17

Jagatheesan, Ganapathy; Rajan, Sudarsan; Petrashevskaya, Natalia; Schwartz, Arnold; Boivin, Greg; Arteaga, Grace; de Tombe, Pieter P; Solaro, R John; Wieczorek, David F (2004. )Physiological significance of troponin T binding domains in striated muscle tropomyosin.American journal of physiology. Heart and circulatory physiology, ,287 (4 ),H1484-94

Prabhakar, Rethinasamy; Petrashevskaya, Natalia; Schwartz, Arnold; Aronow, Bruce; Boivin, Greg P; Molkentin, Jeffery D; Wieczorek, David F (2003. )A mouse model of familial hypertrophic cardiomyopathy caused by a alpha-tropomyosin mutation. Molecular and cellular biochemistry, ,251 (1-2 ),33-42

Jagatheesan, Ganapathy; Rajan, Sudarsan; Petrashevskaya, Natalia; Schwartz, Arnold; Boivin, Greg; Vahebi, Susan; DeTombe, Pieter; Solaro, R John; Labitzke, Erin; Hilliard, George; Wieczorek, David F (2003. )Functional importance of the carboxyl-terminal region of striated muscle tropomyosin.The Journal of biological chemistry, ,278 (25 ),23204-11

Pieples, Kathy; Arteaga, Grace; Solaro, R John; Grupp, Ingrid; Lorenz, John N; Boivin, Greg P; Jagatheesan, Ganapathy; Labitzke, Erin; DeTombe, Pieter P; Konhilas, John P; Irving, Thomas C; Wieczorek, David F (2002. )Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca(2+) activation.American journal of physiology. Heart and circulatory physiology, ,283 (4 ),H1344-53

Prabhakar, R; Boivin, G P; Grupp, I L; Hoit, B; Arteaga, G; Solaro, J R; Wieczorek, D F (2001. )A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.Journal of molecular and cellular cardiology, ,33 (10 ),1815-28

Pieples, K; Wieczorek, D F (2000. )Tropomyosin 3 increases striated muscle isoform diversity. Biochemistry, ,39 (28 ),8291-7

Prabhakar, R; Boivin, G P; Hoit, B; Wieczorek, D F (1999. )Rescue of high expression beta-tropomyosin transgenic mice by 5-propyl-2-thiouracil. Regulating the alpha-myosin heavy chain promoter. The Journal of biological chemistry, ,274 (41 ),29558-63

Muthuchamy, M; Pieples, K; Rethinasamy, P; Hoit, B; Grupp, I L; Boivin, G P; Wolska, B; Evans, C; Solaro, R J; Wieczorek, D F (1999. )Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. Circulation research, ,85 (1 ),47-56

Sussman, M A; Lim, H W; Gude, N; Taigen, T; Olson, E N; Robbins, J; Colbert, M C; Gualberto, A; Wieczorek, D F; Molkentin, J D (1998. )Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science (New York, N.Y.), ,281 (5383 ),1690-3

Muthuchamy, M; Boivin, G P; Grupp, I L; Wieczorek, D F (1998. )Beta-tropomyosin overexpression induces severe cardiac abnormalities.Journal of molecular and cellular cardiology, ,30 (8 ),1545-57

Muthuchamy, M; Rethinasamy, P; Wieczorek, D F (1997. )Tropomyosin structure and function new insights.Trends in cardiovascular medicine, ,7 (4 ),124-8

Muthuchamy, M; Grupp, I L; Grupp, G; O'Toole, B A; Kier, A B; Boivin, G P; Neumann, J; Wieczorek, D F (1995. )Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart. The Journal of biological chemistry, ,270 (51 ),30593-603

Muthuchamy, M; Pajak, L; Howles, P; Doetschman, T; Wieczorek, D F (1993. )Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos. Molecular and cellular biology, ,13 (6 ),3311-23

Muthuchamy, M; Pajak, L; Wieczorek, D F (1992. )Induction of endogenous myosin light chain 1 and cardiac alpha-actin expression in L6E9 cells by MyoD1. The Journal of biological chemistry, ,267 (26 ),18728-34

Diebold, R J; Koch, W J; Ellinor, P T; Wang, J J; Muthuchamy, M; Wieczorek, D F; Schwartz, A (1992. )Mutually exclusive exon splicing of the cardiac calcium channel alpha 1 subunit gene generates developmentally regulated isoforms in the rat heart. Proceedings of the National Academy of Sciences of the United States of America, ,89 (4 ),1497-501

Pajak, L; Mariappan, M; Wieczorek, D F (1991. )Reprogramming of myosin light chain 1/3 expression in muscle heterokaryons. Developmental biology, ,145 (1 ),28-39

Wieczorek, D F; Hughes, S R (1991. )Developmentally regulated cDNA expressed exclusively in neural tissue. Brain research. Molecular brain research, ,10 (1 ),33-41

Hasselgren, P O; Tricoli, J V; Wieczorek, D; Steigerwald, K A; Angerås, U; Hall-Angerås, M; Fischer, J E (1991. )Reduced levels of mRNA for myofibrillar proteins in skeletal muscle from septic rats. Life sciences, ,49 (10 ),753-60

Wieczorek, D F (1988. )Regulation of alternatively spliced alpha-tropomyosin gene expression by nerve extract. The Journal of biological chemistry, ,263 (21 ),10456-63

Rajan S, Pena J, Jegga A, Aronow B, Wolska B, and Wieczorek DF. (2013. )Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescues by a phospholamban knockout .Physiological Genomics, ,

Schulz E and Wieczorek DF (2013. )Tropomyosin de-phosphorylation in the heart: what are the consequences .J Muscle Res Cell Motil, ,

Schulz, Emily M; Wilder, Tanganyika; Chowdhury, Shamim A K; Sheikh, Hajer N; Wolska, Beata M; Solaro, R John; Wieczorek, David F (2013. )Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy.The Journal of biological chemistry, ,288 (40 ),28925-35

Rajan, Sudarsan; Pena, James R; Jegga, Anil G; Aronow, Bruce J; Wolska, Beata M; Wieczorek, David F (2013. )Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout.Physiological genomics, ,45 (17 ),764-73

Schulz, Emily M; Wieczorek, David F (2013. )Tropomyosin de-phosphorylation in the heart: what are the consequences?.Journal of muscle research and cell motility, ,34 (3-4 ),239-46

Wilder, Tanganyika; Ryba, David M; Wieczorek, David F; Wolska, Beata M; Solaro, R John (2015. )N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy.American journal of physiology. Heart and circulatory physiology, ,309 (10 ),H1720-30

Tarigopula, Madhusudhan; Davis, Robert T; Mungai, Paul T; Ryba, David M; Wieczorek, David F; Cowan, Conrad L; Violin, Jonathan D; Wolska, Beata M; Solaro, R John (2015. )Cardiac myosin light chain phosphorylation and inotropic effects of a biased ligand, TRV120023, in a dilated cardiomyopathy model.Cardiovascular research, ,107 (2 ),226-34

Prasad, Vikram; Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L; Huang, Wei; Wang, Yigang; Wieczorek, David W; Shull, Gary E (2015. )SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure.BioMed research international, ,2015 ,251598

Prasad, Vikram; Lorenz, John N; Lasko, Valerie M; Nieman, Michelle L; Jiang, Min; Gao, Xu; Rubinstein, Jack; Wieczorek, David F; Shull, Gary E (2014. )Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology, ,77 ,53-63

Dhoke, M A; Ladha, P J; Boerio, F J; Lessard, L B; Malinowska, D H; Cuppoletti, J; Wieczorek, D S (2005. )Porous membranes for reconstitution of ion channels.Biochimica et biophysica acta, ,1716 (2 ),117-25

Post Graduate Training and Education

Postdoctoral Fellow, Children's Hospital of Boston and Harvard Medical School, ,

Keywords

Heart,Tropomyosin,Histogenesis,Genetic Model,Gene Targeting,Gene Expression,Laboratory Mouse,Transgenic Animal,Genetic Regulation,Embryonic Stem Cell,Restriction Mapping,Tissue Cell Culture,Transfection Vector,Cell Differentiation,Cytoskeletal Protein,Genetic Manipulation,Fibroblast Growth Factor

Contact Information

Academic - 2939 Cardiovascular Center
231 Albert Sabin Way
Cincinnati  Ohio, 45267-0524
Phone: (513)558-0058
Fax: (513)558-1885
david.wieczorek@uc.edu