R01HL163103

Hexosamine biosynthesis pathway metabolism during cardiac hypertrophy - project summary.

A broad range of diseases, from hypertension to structural heart diseases like aortic stenosis or coarctation of the aorta, cause pressure overload stress on the heart. In response, the heart undergoes hypertrophy (called pressure overload hypertrophy or POH) which can promote adaptation or cause heart failure. Understanding the mechanism underlying these opposite clinical outcomes would create new therapeutic opportunities.

The unstressed heart relies mainly on fatty acids for fuel but alters energy sources depending on availability. POH causes the heart to increase its reliance on glucose for energy, but, unfortunately, this metabolic inflexibility impacts hypertrophic growth and ventricular dysfunction. Therefore, improving the balance of sources used for fuel generation during POH could promote adaptation but therapies targeting this approach have not been realized partially because the mechanisms underlying these metabolic changes are incompletely known.

Our preliminary results identified a new mechanism potentially impacting substrate preferences for energy production in the citric acid cycle during POH that we pursue in this proposal. Posttranslational modifications by O-linked SS-N-acetylglucosamine (O-GlcNAc) globally increase in hypertrophied hearts in humans and animals. A widely accepted dogma assumes that the hexosamine biosynthesis pathway (HBP) leading to the O-GlcNAcylation of proteins depends on metabolic changes, especially in glycolytic flux. However, our recent data suggests the reverse; that HBP flux and O-GlcNAc levels determine cardiac fuel utilization. We recently performed the most comprehensive evaluation of protein O-GlcNAc changes during POH and preliminarily identified increased O-GlcNAc levels on multiple enzymes for fatty acids and glucose metabolism. Accordingly, we propose a new paradigm that HBP flux and O-GlcNAc are key regulators of fuel preferences for the citric acid cycle during POH. Thus, O-GlcNAc could potentially be targeted to treat metabolic inflexibility and prevent cardiac maladaptation during POH.

We test our new paradigm with three specific aims:

1) Using transgenic mice, we will evaluate the effect of modifying O-GlcNAc levels on left ventricular function and remodeling in POH.
2) We will determine the effect of modifying O-GlcNAc levels on fatty acid oxidation, glucose oxidation, and glycolysis during POH.
3) We will determine the regulation of HBP flux and O-GlcNAc levels during POH.

Our project provides essential insights into the regulation of fuel sources during POH, along with determining the effects of increased O-GlcNAc levels during POH. This knowledge could help develop new therapeutic approaches to prevent or treat the common clinical problem heart failure from POH. This project addresses key knowledge deficits on the regulation of HBP flux and protein O-GlcNAc during hypertrophy, as well as their functional effects during hypertrophy. They will, therefore, provide essential insights on targeting these mechanisms for preventing or treating heart failure.

Seattle Children's Hospital

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Seattle, Washington 981053901 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 318% from $750,797 to $3,139,981.