In the heart, as in cancer, metabolism provides energy and building blocks for the cell. James Watson (of The Double Helix fame) recently pronounced that in cancer, targeting metabolism may be a more promising approach to treatment than targeting transforming genes. At a time when cellular regeneration receives much attention, the intracellular dynamics of metabolism must be considered as well. In earlier work supported by this grant, we identified two metabolic signals serving as regulators of protein turnover in the heart: a low [ATP] / [AMP] ratio as regulator for protein degradation, and glucose 6-phosphate as regulator of the mTOR growth signaling pathway. We learned that in the heart, like in cancer cells, a phenomenon known as the Warburg Effect drives metabolic rearrangements which are linked to enable cell growth. Perhaps even more importantly, we learned that the oncometabolite D-2-hydroxyglutarate impairs cardiac function by inhibiting a Krebs cycle enzyme. Our overall objective is now to solidify the concept of a link between cancer cell metabolism, and cardiac cell metabolism, cardiac structure, and cardiac function independently from any chemotherapeutic agents or pharmacological interventions.
Specific Aim 1 will define the role of oncometabolic signals as regulators of cardiac remodeling.
Specific Aim 2 will define the role of reductive carboxylation as a mediator for metabolic structural and functional remodeling of the heart using the oncometabolite D-2-hydroxyglutarate as a model.
Specific Aim 3 will extend the findings to address specific structural, proteomic and epigenetic mechanisms of remodeling in the metabolically deregulated state of D-2- hydroxyglutarate. In summary, as we continue our work on the intracellular self-renewal of the cardiomyocyte, we expect to identify new regulatory proteins and enzymes that drive adaptation to metabolic stress in the heart. Our long-term goal is to develop a platform for new metabolic strategies to support the failing human heart by integrating specific, dynamic aspects of cancer cell metabolism with heart metabolism. In short, metabolic systems do not exist in isolation and their understanding may be exploited for the treatment of heart failure.

Public Health Relevance

The defining feature of every cell is the dynamic state of its constituents. Our ongoing work on intracellular self- renewal of the heart has exposed two metabolic pathways, which are prominent in cancer cells and which weaken the heart in the absence of any chemotherapeutic agents. Based on shared features of metabolism we are now proposing to exploit dynamics of metabolic pathways to improve both structure and function of the failing heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061483-17
Application #
9838762
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
1999-01-01
Project End
2021-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
17
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
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