Saturday, May 17, 2025
5/17/2025
Regulation of STAT3 phosphorylation and its role in orienting myocyte hypertrophy - Project Summary/Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with projected numbers continually rising, mandating a need for novel therapeutic approaches. A common feature in the development of HF is hypertrophic growth of cardiac myocytes and associated remodeling of the size, dimensions, and function of the heart. Pathologic hypertrophy initially occurs as an adaptive response, leading to increased width of individual myocytes and causing concentric growth characterized by thickened heart walls, reduced wall strain, and maintained function. Left unchecked, this hypertrophic growth becomes maladaptive and reorients to growth along myocyte length, causing relative wall thinning, heart dilation, and declining function leading to HF. We currently have a poor understanding of the mechanisms which govern this transition, yet, limited observations where adaptive growth is preserved shows resistance to HF development. Therefore, this proposal seeks to identify the fundamental mechanisms underlying adaptive and maladaptive hypertrophic growth and investigate targeted interventions to maintain and/or restore the adaptive state for HF prevention. This proposal will address the critical distinction that not all pathologic hypertrophy is adverse and that preserving the adaptive, concentric state is therapeutically advantageous in response to chronic stress. Preliminary data has implicated a role for the phospho-regulation of the transcription factor STAT3 in mediating this transition. In particular, phosphorylation of the serine residue 727 on STAT3 was revealed as a critical target with dramatic influence over concentric/eccentric growth. Therefore, our central hypothesis is that STAT3 Ser727 phosphorylation is directly responsible for the induction of gene programs which drive adaptive versus maladaptive hypertrophy and represents a therapeutic target in HF treatment. The approach will be to: 1) Determine the molecular mechanism linking STAT3 Ser727 phospho-regulation to hypertrophic orientation. 2) Define novel gene targets and pathways which tune cardiac myocyte growth and hypertrophy. Specifically, this approach will address altered STAT3 transcriptional activity dependent on Ser727 phosphorylation through ChIP-seq and RNA-seq to identify gene programs which enact concentric/eccentric states. 3) Lastly, we will test novel therapeutic strategies to support adaptive cardiac remodeling during pathologic hypertrophy in vivo to assess effectiveness in HF prevention. Overall, we anticipate that these data will expand our understanding of HF remodeling, delineate the nature of adaptive, concentric hypertrophy, and reveal novel therapeutic opportunity in HF. Furthermore, characterization of STAT3 phospho-regulation and transcriptional activity will provide significant pathophysiologic insight to numerous other disease states such as cancer, fibrosis, inflammation, and immune signaling where STAT3 activity has been implicated.
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