[F31] SGK1: A novel target for atrial myopathy in HFpEF
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-06-30
Importo max: 40.907 EUR
Paese: US
Descrizione
Project Summary
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 SG
Istituzione: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
PI: Alina Bilal
Progetto: 1F31HL184588-01
Settori: National Heart Lung and Blood Institute
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