Metabolic regulation of neutrophil function
Active Project Grant Awarded Last action
- Award ID
- F31HL186605
- Recipient
-
University Of Louisville UEI E1KJM4T54MK6
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $37,174
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 0% complete
- Place of performance
- Louisville, KY 40202, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cardiac repair following myocardial infarction (MI) depends on a tightly regulated inflammatory response that clears necrotic tissue and promotes scar formation. Neutrophils are the first immune cells to infiltrate the injured myocardium and are essential for wound healing; however, excessive or prolonged neutrophil activation exacerbates tissue damage and contributes to adverse remodeling. Upon activation, neutrophils recruit and coordinate several effector functions, including production of reactive oxygen species (ROS), release of granular proteases, extrusion of neutrophil extracellular traps (NETS), and secretion of proinflammatory cytokines. Although these neutrophil effector functions likely evolved to improve chances of survival due to infection, such hypervigilant responses could be deleterious for tissue repair after sterile injuries, such as MI. Because neutrophils are terminally differentiated and have a short lifespan, they have a limited ability to regulate their responses via gene transcription. Instead, neutrophils exploit metabolic control mechanisms to coordinate and fine-tune their responses to tissue infection or injury. Although activation of the oxidative pentose phosphate pathway and glycolysis are known to be essential for effector functions such as the respiratory burst and for providing cellular energy, IT is likely that neutrophils leverage other forms of metabolic control to titrate the nature and extent of their response to tissue damage. Our preliminary data reveal that activated neutrophils recruit the glycerol 3-phosphate (G3P) shuttle to sustain mitochondrial membrane potential and to promote ROS formation, which is important for effector functions such as netosis. Accordingly, we propose that the neutrophil G3P shuttle contributes to a hyperinflammatory response after MI by promoting mitochondrial ROS formation, which is essential for net release and intensifies immune cell recruitment, prolongs inflammation, and promotes excessive fibrosis, thereby contributing to excessive fibrosis and ventricular dilation. To test this hypothesis, we will: (1) determine how the G3P shuttle influences neutrophil effector function; and (2) elucidate the impact of the neutrophil G3P shuttle on ventricular inflammation and remodeling after MI. Collectively, this work will uncover fundamental metabolic mechanisms that regulate neutrophil responses to injury and define their impact on cardiac repair. These insights may inform new therapeutic strategies to optimize inflammation and resolution and improve post-MI outcomes. As a training vehicle, the techniques and strategies in this project will catalyze my development, providing knowledge and expertise essential for the development of an independent career in research.
Quick answers
Who received award F31HL186605?
F31HL186605 was awarded to University Of Louisville by National Heart Lung and Blood Institute (National Institutes of Health) on January 15, 2027.
How much is award F31HL186605 worth?
$37,174 has been obligated on F31HL186605.
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