Heart failure (HF) remains a major source of morbidity and mortality in the U.S., affecting an estimated 5.7 million Americans with growing prevalence. Maladaptive remodeling is an important step in the progression of HF and is driven by a constellation of cell- and tissue-level factors including hypertrophic growth, inflammation, fibrosis and genetic reprogramming. While great strides have been made in identifying membrane receptors, signaling proteins, transcription factors, and other molecules involved in adverse remodeling, fundamental questions remain about the molecular pathways linking extracellular stress cues to cellular reprogramming in disease. Spectrins are important for membrane integrity and ultrastructure in a wide variety of cells, including myocytes. Recent studies demonstrate novel roles for βIV-spectrin in regulating heart function through the organization of local signaling domains. Specifically, we have shown that βIV-spectrin targets CaMKII to substrates at the intercalated disc. We have identified alterations in spectrins and spectrin-based pathways in human HF and animal models of HF, although the functional consequences are unknown and untested. This proposal is motivated by unanticipated and exciting preliminary data linking βIV-spectrin to signal transducer and activator of transcription 3 (STAT3), a ubiquitous stress-activated transcription factor that regulates gene programs important in physiological and pathological forms of cardiac hypertrophy. Our data define a novel, direct interaction between βIV-spectrin and STAT3, in vitro and in vivo, that is essential for maintaining balanced STAT3 signaling. Furthermore, our studies indicate that loss of βIV-spectrin in animals and human heart failure promotes cellular redistribution of STAT3, altered gene expression leading to pathological remodeling changes at the cell- and tissue-level, and cardiac dysfunction. Finally, our data support that targeted disruption of CaMKII-dependent regulation of the spectrin-based statosome prevents STAT3 dysregulation, mitigates maladaptive remodeling, and preserves cardiac function in response to chronic stress. These data provide a potential link between spectrin dysfunction and remodeling in HF, and establish a new paradigm for cardiac βIV-spectrin as a critical regulatory node in a transcriptional highway for stress-induced cellular reprogramming in heart. Our long-term goal is to define new regulatory pathways underlying adverse remodeling in HF, and to test whether they may be manipulated for therapeutic benefit. Our central hypothesis is that βIV-spectrin is required for maintaining balanced STAT3 activity in heart and that spectrin dysfunction promotes aberrant STAT3 signaling, cell reprogramming, and adverse remodeling in chronic disease.