The identification of intracellular signal transduction pathways that regulate pathologic cardiac growth has been an area of intense interest. The identification of these pathways would establish novel targets, modulation of which could alter the progression of hypertrophy to heart failure. This has been a difficult goal to achieve, however, since it is apparent that multiple interacting and/or parallel pathways regulate growth of the heart. Our interests have focused on the glycogen synthase kinase-3 pathway. We have found that GSK-3 is a negative regulator of cardiac growth. We have created a transgenic mouse expressing GSK-3beta in the heart, and this mouse is characterized by markedly impaired cardiac growth. We have also followed the GSK-3 pathway downstream to identify targets of GSK-3 that may play a role in growth. We have now identified one target, beta-catenin, that is negatively regulated by GSK-3. Beta-catenin is a transcription factor that has been known for some time to regulate dorsoventral patterning during embryoganesis as part of the Wnt pathway. In addition, mutations in beta-catenin have been found in a number of cancers, attesting to its role in tumorigenesis. We propose three Specific Aims to further clarify the role of GSK-3beta and beta-catenin in normal and pathologic cardiomyocyte growth.
Specific Aim 1. Determine the role of beta-catenin in the development of cardiac hypertrophy. It is our hypothesis that beta-catenin is a critical regulator of physiologic and pathologic hypertrophy in vivo. We will determine whether beta-catenin is necessary, sufficient, or both, for the hypertrophic response in vivo using a variety of approaches including viral mediated gene transfer, transgenic models, and a cardiac-specific conditional knockout of beta-catenin.
Specific Aim 2. Determine the mechanisms by which expression of GSK-3beta leads to a phenotype of impaired growth and depressed systolic function of the heart. GSK-3beta has a number of targets, any of which could play a role in impaired growth. It is our hypothesis that GSK-3beta blocks physiologic hypertrophy primarily via its inhibitory effects on the beta-catenin/c-Myc pathway. We will evaluate this hypothesis, again employing viralmediated gene transfer, transgenics, and knockouts.
Specific Aim 3. Determine the mechanisms regulating beta-catenin stabilization in response to hypertrophic stress. Our preliminary studies have identified a novel mechanism by which beta-catenin is stabilized by hypertrophic stress, and this involves recruitment of the GSK-3beta inhibitor, PKB/Akt to the beta-catenin degradation complex. It is our hypothesis that the mechanism involves recruitment of downstream components of the Wnt pathway. We will attempt to identify the specific signaling factors involved. We believe that the studies outlined herein, which are a logical extension of the work performed under this grant over the past three years, will allow us to define a novel linear signaling pathway, including cytosolic and nuclear components, regulating physiologic and pathologic hypertrophy of the heart.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Reinlib, Leslie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
United States
Zip Code
Zhou, Jibin; Ahmad, Firdos; Parikh, Shan et al. (2016) Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. Circ Res 118:1208-22
Zhou, Jibin; Ahmad, Firdos; Lal, Hind et al. (2016) Response by Zhou et al to Letter Regarding Article, ""Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy"". Circ Res 119:e29-e30
Lal, Hind; Ahmad, Firdos; Woodgett, James et al. (2015) The GSK-3 family as therapeutic target for myocardial diseases. Circ Res 116:138-49
Lal, Hind; Ahmad, Firdos; Parikh, Shan et al. (2014) Troponin I-interacting protein kinase: a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease. Circ J 78:1514-9
Lal, Hind; Ahmad, Firdos; Zhou, Jibin et al. (2014) Cardiac fibroblast glycogen synthase kinase-3? regulates ventricular remodeling and dysfunction in ischemic heart. Circulation 130:419-30
Ahmad, Firdos; Lal, Hind; Zhou, Jibin et al. (2014) Cardiomyocyte-specific deletion of Gsk3? mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64:696-706
Zhou, Jibin; Freeman, Theresa A; Ahmad, Firdos et al. (2013) GSK-3? is a central regulator of age-related pathologies in mice. J Clin Invest 123:1821-32
Ky, Bonnie; Vejpongsa, Pimprapa; Yeh, Edward T H et al. (2013) Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res 113:754-64
Lal, Hind; Kolaja, Kyle L; Force, Thomas (2013) Cancer genetics and the cardiotoxicity of the therapeutics. J Am Coll Cardiol 61:267-74
Vagnozzi, Ronald J; Gatto Jr, Gregory J; Kallander, Lara S et al. (2013) Inhibition of the cardiomyocyte-specific kinase TNNI3K limits oxidative stress, injury, and adverse remodeling in the ischemic heart. Sci Transl Med 5:207ra141

Showing the most recent 10 out of 43 publications