Cardiac hypertrophy is primarily an adaptive process, involving growth and survival of cardiomyocytes, in response to an increased hemodynamic load. Although hypertrophy is considered an initial compensatory process, a yet undefined derailment eventually leads to compromised pump function (decompensation) and culminates in congestive heart failure (CHF). Therefore, understanding the mechanism(s) that underlie cardioprotection and growth in both compensatory and decompensatory phases of cardiac hypertrophy is critical in identifying molecular targets for clinical intervention to treat CHF. In the current application, we propose to characterize the specific downstream elements of mTOR (mammalian target of rapamycin), which orchestrates both these processes. mTOR has been described as a cellular sensor of nutrition and energy status, a mediator of hormone-induced growth and is uniquely positioned to organize components regulating translational machinery, cell size, and deleterious protein removal via the ubiquitin-proteasome system (UPS). Indeed, recent studies indicate that the increased synthesis of necessary proteins and degradation of deleterious ones are tightly regulated for protection and growth of cardiomyocytes. Recent studies indicate that mTOR has both rapamycin-insensitive and sensitive kinase functions by forming two distinct multiprotein complexes: mTORC2, which promotes removal of deleterious cellular proteins that are potential targets of Akt (protein kinase B) via UPS, and mTORC1, which regulates protein translation and cell size via molecules such as S6K1 and its recently identified substrate, SKAR (S6K1 Aly/REF-like target). During pressure-overload (PO) induced cardiac hypertrophy, we have shown 1) an increased activation of mTOR, 2) a robust increase in the level of protein ubiquitination and E3 ligases 3) enhanced ribosomal protein synthesis and activation of SKAR, Therefore, our overall hypothesis is that mTORC2 and mTORC1 contribute to both cardiocyte protection and growth in a coordinated manner in the compensatory phase of the hypertrophic growth process and that the augmentation of mTORC2 formation with rapamycin may serve to sustain this compensatory process and improve ventricular function during PO. To test this hypothesis, we propose three Specific Aims: 1) Characterize the ubiquitinated mTORC2/Akt target proteins whose UPS-mediated degradation offers cardioprotection, 2) Characterize the role of a newly described mTORC1/S6K1 target, SKAR, on cell size and growth of hypertrophying cardiomyocytes, and 3) Demonstrate whether PO alters the balance between mTORC1 and mTORC2 and establish whether promoting mTORC2 function by rapamycin contributes to cardioprotection. These studies are envisioned to open new avenues of research into how the mTOR complexes influence hypertrophic growth and identify novel cardio-therapeutic strategies for rapamycin

Public Health Relevance

Hypertrophic cardiomyopathy results from the inability of the heart to compensate for the increased load applied on the heart by means of pressure or volume overload. Defects in growth and survival of the cardiomyocytes are the underlying phenomenon for such disease conditions. Proteins such as mTOR (mammalian target of rapamycin) are centrally located to regulate cell growth and survival pathways during hypertrophy. This study will examine the role of specific targets of mTOR that regulate these processes in cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092124-02
Application #
7751788
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Liang, Isabella Y
Project Start
2008-12-19
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$368,750
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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