SGK1: a novel target for atrial myopathy in hfpef

Active Project Grant Awarded Last action

Award ID
F31HL184588
Recipient
Awarding agency
Obligated
$81,814

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Originally
Place of performance
Salt Lake City, UT 84112, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Heart failure with preserved ejection fraction (HFPEF) represents more than 50% of all heart failure patients and, currently, the only evidence-based therapies for HFPEF are those that target its comorbidities associated with global metabolic syndrome (e.g. SGLT2 inhibitors). Notably, HFPEF uniquely affects the cardiac atria independent of ventricular dysfunction and pulmonary congestion where in atrial myocytes IT leads to structural remodeling and atrial fibrillation (AF). And given the striking prevalence of AF that often precedes ventricular dysfunction in HFPEF patients, AF is now used as a diagnostic measure and primary prognostic indicator of HFPEF pathogenesis, underscoring the need to determine the molecular mechanisms contributing to atrial dysfunction and AF in HFPEF. Recent evidence has shown that global overexpression of the serine-threonine kinase, serum glucocorticoid regulated kinase 1 (SGK1), induces AF in an obese mouse model. SGK1 is further implicated in metabolic dysfunction, where an SGK1 polymorphism present in more than 5% of the global population has been shown to be highly associated with type II diabetes and obesity. In preliminary data generated for this proposal, phosphoproteomic profiling of mouse hearts implicate SGK1 as a primary regulator of cardiac metabolism and cardiac-specific knockout of SGK1 protects against atrial structural remodeling and AF inducibility in a mouse model of HFPEF. Previous studies in our laboratory identified SGK1 as a substrate for rapid proteasome-mediated degradation as a means to mitigate pathological cardiac hypertrophy. We leveraged these findings to design a novel SGK1-inhibitory peptide that promotes proteasome-mediated degradation of SGK1 with therapeutic potential for targeting atrial remodeling in HFPEF. While there is a clear connection between SGK1 and obesity-related AF, neither a role for SGK1 in HFPEF-induced AF nor the mechanism by which SGK1 regulates atrial function have been investigated. In this proposal, I will focus on SGK1 in atrial myocytes in HFPEF with the hypothesis that SGK1 promotes atrial structural and metabolic remodeling as well as increased AF inducibility in response to HFPEF. This hypothesis will be examined using atrial-specific gene targeting of SGK1 in a mouse model of HFPEF with a focus on assessments of atrial structural and metabolic remodeling, as well as mechanistic studies in primary atrial myocytes in the following specific aims which are to: (aim 1) examine the effects of atrial-specific SGK1 loss-of-function on pathological atrial metabolic inflexibility, structural remodeling, and AF inducibility during HFPEF, and (aim 2) evaluate the therapeutic efficacy of a novel SGK1 inhibitory peptide for preserving atrial metabolism, structure and function during HFPEF. These studies are significant as they will comprehensively examine mechanistic roles for SGK1 and allow for the characterization of a novel therapy in the form of a SGK1-inhibitory peptide for AF in HFPEF.

Transactions

Action Obligated Date
Amendment $40,907
Amendment $0
Original award $40,907

Quick answers

Who received award F31HL184588?

F31HL184588 was awarded to University Of Utah by National Heart Lung and Blood Institute (National Institutes of Health) on December 1, 2026.

How much is award F31HL184588 worth?

$81,814 has been obligated on F31HL184588.

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