Hexosamine biosynthesis pathway metabolism during cardiac hypertrophy

Active Project Grant Awarded Last action

Award ID
R01HL163103
Recipient
Awarding agency
Obligated
$10,121,543

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 77% complete
Place of performance
Seattle, WA 98105, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 of 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.

Transactions

Action Obligated Date
Amendment $23,368
Amendment $740,074
Amendment $740,074
Amendment $81,713
Amendment $81,713
Amendment $81,713
Amendment $735,425
Amendment $735,425
Amendment $735,425
Amendment $735,425
Amendment $67,916
Amendment $67,916
Amendment $764,056
Amendment $764,056
Amendment $764,056
Amendment $750,797
Amendment $750,797
Amendment $750,797
Original award $750,797
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Subawards

Subrecipient Amount Awarded
University Of Washington In year 1 we will process 88 freeze-clamped heart samples and acquire 13C-NMR spectra of tissue extracts. The NMR data will be analyzed and presented as %… $50,461
Institut De Cardiologie De Montreal A total of 840 samples will be analyzed for the various experiments using the following methods by GC-MS and LC-MS. We will also provide assistance for data… $62,082
Institut De Cardiologie De Montreal $31,041

Quick answers

Who received award R01HL163103?

R01HL163103 was awarded to Seattle Children's Hospital by National Heart Lung and Blood Institute (National Institutes of Health) on December 20, 2022.

How much is award R01HL163103 worth?

$10,121,543 has been obligated on R01HL163103.

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