Mark's Page
My research concerns mechanisms which regulate the assembly, organization, and degeneration of myofibrils. Proper function of myofibrils depends upon accurate assembly and maintenance of sarcomeric structure. One area of my studies is directed at understanding the formation, stabilization, and breakdown of sarcomeric actin filaments in cardiomyocytes (the muscle cells of the heart). We are investigating regulatory mechanisms which are critical for accurate actin filament organization involving tropomodulin-mediated changes as well as the role of signalling pathways. Adenoviral vectors and transgenic mice are used to study the effect of altering sarcomeric component expression or signalling protein activity upon cardiac myofibril structure.
In addition to these studies of myofibril structure in the myocardium, my research also extends to examination of focal adhesion complex regulation. Maintenence of cellular adhesion is critical for effective transmission of contractile force from the myofibrils to the myocardial wall. Ongoing studies are directed at defining the relationship between focal adhesion structure and the pathogenesis of cardiomyopathy including the rac expressing transgenic created in my lab. Loss of focal adhesion organization is likely to be an important factor contributing to impaired contractility in the dilated heart.
Another area of our research is concerned with preventing cell death that accompanies heart failure. Cell death is a contributory factor in loss of heart function following a heart attack or in the pathogenesis of chronic heart disease. We are working on molecular signaling pathways that inhibit the death of cardiomyocytes, thereby improving cardiac function and slowing the development of heart failure. Our recent work suggests that the pathways we are studying may be partially responsible for gender-dependent differences in cardiovascular disease risk known to exist between men and women.
Most recently we have turned our attention to the area of cardiac regeneration and the potentiation of cardiac progenitor cells to repair damaged myocardium. These studies evolved from our investigations of cell survival and make use of adult cardiac stem cell populations to regenerate and repair myocardial tissue. The enhancement of stem cell activity is critical in order to move these approaches to a clinically-relevant treatment approach for heart disease. these investigations have led us into the area of nuclear trafficking of signaling molecules, which hold important clues to the regulation of cell survival, proliferation, and differentiation.
Biochemistry, molecular biology, and computer-enhanced confocal laser scanning microscopy are all used in combination to study these changes. Since myofibril degeneration and cytoskeletal remodeling are important pathological processes in many types of cardiomyopathy, we are working to create laboratory models of cardiac disease by influencing actin filaments and cytoskeletal stability. In addition ot myofibrils, many cellular structures and tissues depend upon precise actin filament length regulation and organization for proper function. The control of actin filament stability is a central issue in cell biology which impacts upon diverse areas such as differentiation, learning and memory, and tumorigenesis.
Sussman MA, Bilak M, Kedes LH, Engel WK and Askanas
V. Tropomodulin is highly concentrated at the post-synaptic domain of
human and rat neuromuscular junctions. Exp. Cell Res. 1993;
209: 389-391.
Sussman MA, Sakhi S, Tocco G, Najm I, Baudry M,
Kedes LH and Schreiber S. Neural tropomodulin: developmental expression
and effect of seizure activity. Brain Res. (Dev. Brain Res.)
1994; 80: 45-53.
Sussman MA, Sakhi S, Barrientos P, Ito M and Kedes
LH. Tropomodulin in rat cardiac muscle:localization of protein is
independent of mRNA distribution during myofibrillar development. Circ.
Res. 1994; 75: 221-232.
Ito M, Swanson B, Sussman MA,
Lyons G and Kedes LH.Cloning of tropomodulin cDNA and localization of
gene transcripts during mouse embyrogenesis. Dev. Biol.
1995; 167: 317-328.
Przyklenk K, Sussman MA,
Simkhovich BZ and Kloner RA. Does activation of protein kinase C
mediate ischemic preconditioning in the canine model? Circ.1995;
92: 1546-1557.
Sussman MA, Ito M, Daniels MP,
Flucher B, Buranen S and Kedes LH. Chicken skeletal muscle
tropomodulin: novel localization and characterization. Cell
Tissue Res. 1996; 285: 287-296.
Sussman MA, McAvoy JW, Rudisill M, Swanson B, Lyons
GE, Kedes L and Blanks J. Lens tropomodulin: developmental expression
during differentiation. Exp. Eye Res. 1996; 63: 223-232.
Sussman MA. Analysis of myofibrillar organization
and degeneration by fluorescence confocal microscopy. Proc.
Microscopy and Microanalysis 1996; 18-19.
Sussman MA, Hamm-Alvarez S, Vilalta P, Welch S and
Kedes L. Involvement of phosphorylation in doxorubicin-mediated
myofibril degeneration: an immunofluorescence microscopy analysis. Circ.
Res. 1997; 80: 52-61.
Cambon N and Sussman MA.
Isolation and preparation of single mouse cardiomyocytes for confocal
microscopy. Meth. Cell Sci. 1997; 19: 83-90.
Sussman MA, Baque S, Uhm C-S, Daniels MP, Price RL,
Simpson D, Terracio L and Kedes L. Altered expression of tropomodulin
in cardiomyocytes disrupts the sarcomeric structure of myofibrils.
Circ. Res. 1998; 82: 94-105.
Sussman MA, Welch S, Cambon N, Klevitsky R, Hewett
TE, Price RL, Witt SA and Kimball TR. Myofibril degeneration caused by
tropomodulin overexpression leads to dilated cardiomyopathy in juvenile
mice. J. Clin. Invest. 1998; 101: 51-61.
Sussman MA, Lim
HW, Gude N, Taigen T, Olson EN, Robbins J, Colbert MC, Gualberto A,
Wieczorek DF and Molkentin JD. Prevention of cardiac hypertrophy in
mice by calcineurin inhibition. Science 1998; 281:
1690-1693.
Sussman MA, Welch
S, Gude N, Khoury PR, Daniels SR, Kirkpatrick D, Walsh RA, Price RL,
Lim HW and Molkentin JD. Pathogenesis of dilated cardiomyopathy:
molecular, structural, and population analyses in tropomodulin
overexpressing transgenics. Am. J. Pathol. 1999; 155:
2101-2111.
Sussman MA, Welch
S, Walker A, Klevitsky R, Hewett TE, Witt SA, Kimball TR, Price R, Lim
HW and Molkentin JD. Hypertrophic defect unmasked by calcineurin
expression in asymptomatic tropomodulin overexpressing transgenic mice. Cardiovasc.
Res. 2000; 46: 90-101.
Lim HW, DeWindt LJ, Marte J, Kimball TR, Witt
SA, Sussman MA and Molkentin JD. Reversal of cardiac
hypertrophy in transgenic disease models by calcineurin inhibition. J.
Mol. Cell Cardiol. 2000; 32: 697-709.
Sussman MA, Welch
S, Walker A, Klevitsky R, Hewett TE, Price RL, Schaefer E and Yager K.
Myocardial rac1 activation in transgenic mice: altered focal adhesion
regulation correlates with cardiomyopathy. J. Clin. Invest. 2000;
105: 875-886.
Babu GJ, Lalli MJ, Sussman MA,
Sadoshima J and Periasamy M. Phosphorylation of elk-1 by MEK/ERK
pathway is necessary for c-fos gene activation during cardiac myocyte
hypertrophy. J. Mol. Cell Cardiol. 2000; 32: 1447-1457.
Greene AL, Lalli MJ, Ji Y, Babu GJ, Grupp I, Sussman
MA, and Periasamy M. Overexpression of SERCA2b in the heart
leads to an increase in calcium transport function and increased
cardiac contractility. J. Biol. Chem. 2000; 275:
24722-24727.
Delling U, Sussman MA and Molkentin JD.
Re-evaluating sarcoplasmic reticulum function in heart failure. Nature
Med. 2000; 6: 942-943.
Yang J, Moravec CS, Sussman MA, DiPaola
NR, Fu D, Hawthorn L, Mitchell CA, Young JB, Francis GS, McCarthy PM
and Bond M. Decreased SLIM1 expression and increased gelsolin
expression in failing human hearts measured by high density
oligonucleotide arrays. Circulation 2000; 102: 3046-3052.
Camper-Kirby D, Welch S, Walker A, Shiraishi
I, Setchell KDR, Schaefer E, Kajstura J, Anversa P and Sussman MA.
Myocardial Akt activation and gender: increased nuclear activity in
females versus males. Circ Res. 2001; 88: 1020-1027
Ehler E, Horowits R, Zuppinger C, Price RL,
Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM and
Perriard J-C. Alterations at the intercalated disk associated with the
absence of muscle LIM protein. J. Cell Biol. 2001; 153:
763-772.
Lalli MJ, Yong J, Plank D, Prasad V, Hashimoto
K, Babu GJ, Kirkpatrick D, Loukianov E, Walsh RA, Sussman M,
Yatani A, Marban E and Periasamy M. SERCA1a structurally substitutes
for SERCA2a in the sarcoplasmic reticulum and increases cardiac Ca2+
handling capacity. Circ. Res. 2001; 89: 160-167.
Sussman MA. When
the thyroid speaks, the heart listens. (Editorial). Circ. Res.
2001; 89: 557-559.
Sussman MA.
Cellular indigestion: chaperones head to the cytoskeleton. (Editorial). J
Mol. Cell. Cardiol. 2002; 34: 83-85.
Welch S, Plank D, Witt S, Glascock B, Chimenti
S, Andreoli AM, Limana F, Leri A, Kajstura J, Anversa P and Sussman
MA. Cardiac-specificIGF-1 expression attenuates dilated
cardiomyopathy in Tropomodulin Overexpressing Transgenic mice. Circ.
Res. 2002; 90: 649-656.
Belecky-Adams T, Holmes M, Shan Y, Tedesco CS,
Mascari C, Kaul A, Wight DC, Morris RE, Sussman M, Diamond J
and Parysek L. An intact intermediate filament network is required for
collateral sprouting of small diameter nerve fibers. J. Neurosci.
2003; 23: 9312-9319.
