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Reduced Complex N-Glycosylation, β-Adrenergic Receptor Sensitivity, and Heart Failure

Award Number: R15HL188532
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Reduced Complex N-Glycosylation, β-Adrenergic Receptor Sensitivity, and Heart Failure - Heart failure (HF) affects over 64 million people worldwide and remains a leading cause of morbidity, mortality, and healthcare cost. Despite therapeutic advances, current treatments mainly alleviate symptoms rather than target upstream molecular events that initiate disease. Chronic β₁-adrenergic receptor (β₁-AR) activation is a hallmark of HF progression, yet the mechanisms that sensitize β₁-ARs and convert adaptive to maladaptive signaling remain unclear. We propose a new mechanistic concept: loss of complex N-glycosylation enhances β₁-AR signaling and triggers disease onset. Reduced complex N-glycosylation is linked to aging and cardiovascular disease and may prime cardiomyocytes for β₁-AR hyperactivation even without excessive sympathetic drive. This would promote early Ca2⁺ dysregulation, hypercontractility, and energetic mismatch that initiate HF. The glycosyltransferase Mgat1, which initiates complex N-glycan synthesis, is markedly reduced in human end-stage cardiomyopathy. In cardiomyocyte-specific Mgat1 knockout models, reduced complex N- glycosylation augments β₁-AR–dependent Ca2⁺ signaling and contractility, producing early hypercontractility, electrical instability, and progressive ventricular dysfunction. These findings identify altered glycosylation as an upstream switch that amplifies β₁-AR activity and accelerates the transition from compensated to failing myocardium. We will test the hypothesis that loss of complex N-glycosylation enhances β₁-AR signaling, triggering early hypercontractility that precipitates electromechanical dysfunction and accelerates HF progression through three aims: 1) Determine how reduced N-glycosylation accelerates β₁-AR–dependent electromechanical dysfunction during disease onset; 2) Determine whether reduced glycosylation biases β₁-AR signaling toward maladaptive stress and remodeling pathways; and 3) Determine whether these mechanisms are conserved in human HF tissue. Mechanistic studies will integrate echocardiography, optical mapping, Ca2⁺ imaging, glycomic, and biochemical approaches at molecular, cellular, and organ levels to define how altered glycosylation modifies β₁-AR signaling and cardiac performance. This project is innovative because it defines glycosylation as a previously unrecognized regulator of β₁-AR signaling and cardiac electromechanical activity, linking protein processing to adrenergic signaling and HF onset. Analyses of human ventricular tissue will assess whether these glycosylation-dependent effects are conserved clinically, identifying potential early biomarkers of HF progression. Through mentored participation in molecular, imaging, and physiological studies, students will gain hands-on training in cardiovascular research techniques and data interpretation. These experiences will prepare a new generation of biomedical scientists and expand the research culture at Wright State University. The combined scientific and educational impact will strengthen our NIH-funded research foundation and reveal new mechanistic entry points for HF prevention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $552,338 )
2026	2026	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Cardiovascular Diseases Research	000	1	8/13/2026	NEW	$552,338
														Subtotal = $552,338

Grand Total All Awards = $552,338

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Reduced Complex N-Glycosylation, β-Adrenergic Receptor Sensitivity, and Heart Failure

Award Number: R15HL188532

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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