verbatim): Cardiomyopathy is characterized by structural remodeling of the heart that ultimately results in maladaptive functional consequences. Since cardiac function and structure are interdependent, optimal treatment strategies must approach the long term goal of limiting structural degeneration in progressive heart disease. Cardiac remodeling depends upon molecular signaling that regulates both cellular shape and adhesion by altering the membrane-associated cytoskeleton. The cytoskeleton transduces chemical signals into physical organization and adhesion, so control of cytoskeletal integrity is essential for normal growth and function. Cytoskeletal abnormalities are common in cardiomyopathic cells, but the relationship between cytoskeleton integrity and associated regulatory signaling pathways is poorly understood. The hypothesis of this proposal is that cytoskeletal reorganization is an integral part of the remodeling process during compensation, but that altered regulation of remodeling contributes to loss of adhesion and cardiac failure.
The specific aims are: 1) Determine the molecular pathways regulating focal adhesions that are altered in murine (TOT and racET) and human cardiac failure; 2) Activate focal adhesion signal transduction pathways in vitro and correlate with cardiomyocyte cytoskeletal reorganization; 3) Modulate focal adhesion signal transduction pathways with selective pharmacologic inhibitors and correlate with altered pathogenesis in vivo as well as cardiomyocyte cytoskeletal reorganization in vitro. Biochemical, molecular, and confocal microscopic approaches will combine to identify participants in adhesion regulation, effects upon cardiomyocyte architecture, and impact of inhibitory treatments. The significance is integration of new knowledge regarding cytoskeletal regulation in cardiac remodeling and failure into our understanding of myocardial signal transduction. Results of this study will identify molecular regulators of dilation and open new potential therapeutic targets for pharmaceutical intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066035-03
Application #
6637537
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Reinlib, Leslie
Project Start
2001-04-15
Project End
2003-06-30
Budget Start
2003-03-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2003
Total Cost
$101,013
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Sussman, Mark A (2017) A Matter of Opinion. Circ Res 120:36-38
Sussman, Mark A; Murry, Charles E (2008) Bones of contention: marrow-derived cells in myocardial regeneration. J Mol Cell Cardiol 44:950-3
Tsujita, Yasuyuki; Muraski, John; Shiraishi, Isao et al. (2006) Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 103:11946-51
Plank, David M; Sussman, Mark A (2005) Impaired intracellular Ca2+ dynamics in live cardiomyocytes revealed by rapid line scan confocal microscopy. Microsc Microanal 11:235-43
Kato, Takahiro; Muraski, John; Chen, Yan et al. (2005) Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt. J Clin Invest 115:2716-30
Steinberg, Susan F; Sussman, Mark A (2005) Cardiac hypertrophy served with protein kinase Cepsilon: delta isoform substitution available at additional cost. Circ Res 96:711-3
Tsujita, Yasuyuki; Kato, Takahiro; Sussman, Mark A (2005) Evaluation of left ventricular function in cardiomyopathic mice by tissue Doppler and color M-mode Doppler echocardiography. Echocardiography 22:245-53
Shiraishi, Isao; Melendez, Jaime; Ahn, Youngkeun et al. (2004) Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ Res 94:884-91
Plank, David M; Yatani, Atsuko; Ritsu, Honda et al. (2003) Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade. Am J Physiol Heart Circ Physiol 285:H305-15
Plank, David M; Sussman, Mark A (2003) Intracellular Ca2+ measurements in live cells by rapid line scan confocal microscopy: simplified calibration methodology. Methods Cell Sci 25:123-33

Showing the most recent 10 out of 14 publications