Heart failure (HF) is poorly treated by current therapies. More knowledge of the deleterious mechanisms that produce this disease is necessary in order to develop novel specific therapies. The focus of this research is on testing therapeutic approaches targeting maladaptive mechanisms that will improve impaired contractility and deficient energy production in HF. Our long-term goal is to identify new highly specific therapeutic targets to treat HF. Our immediate goals are to determine if reducing excessive protein OGlcNAcylation to normal can improve cardiac function in HF. Our preliminary results show that in HF nuclear, cytosolic, sarcoplasmic reticulum (SR) and mitochondrial (Mito) cardiac proteins are excessively OGlcNAcylated. Furthermore, reducing O-GlcNAcylation by transgene expression in mice with HF resulted in improved cardiac function. The hypothesis is that HF-induced abnormalities in cardiac myoc)1:es (CM) can be reverted by expression of specific transgenes that correct the maladaptive excessive protein OGlcNAcylation and/or its deletrious effects on key myocardial proteins. Using viral vector gene transfer in a mouse model of HF, or transgenic mice with HF the following specific goals should be achieved: i) Identify and determine the time course and mechanisms contributing to excessive 0-GlcNAcylation of proteins in the intact CM and in specific organelles of the CM during the evolution of PO-induced HF. 2) Determine if attenuation or reversal of excessive CM protein 0-GlcNAcylation improves function in the failing heart. 3) Establish that excessive 0-GlcNAcylation of specific proteins diminishes Mito function and propagates HF.
In Aim I the mechanisms contributing to excessive protein 0-GlcNAcylation in HF are explored and key cardiac proteins that undergo excessive 0-GlcNAcylation are identified.
Aim I is related to Aim II, in that in Aim II we determine if reversal of excessive nuclear, cytosolic and SR protein 0-GlcNAcylation in CM of HF improves CM and heart function.
Aim III establishes that excessive 0-GlcNAcylation of specific proteins diminishes Mito function.

Public Health Relevance

Heart failure is a significant health problem in the U.S. and is poorly treated by current therapies. Results generated in this study will have a positive impact in our knowledge of the mechanisms that cause heart failure. In addition, therapeutic approaches targeting these novel mechanisms will reveal new potential treatments for this important disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL066941-11A1
Application #
8647154
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-09-26
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$421,504
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
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