PROJECT SUMMARY / ABSTRACT Inherited mutations in sarcomeric genes, which decrease cardiac myocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)– the leading cause of heart failure. Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been entirely cardiac myocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis. Our recent findings in a mouse model of inherited DCM demonstrated that prior to the onset of fibrosis and dilated myocyte remodeling both the myocardium and extracellular matrix (ECM) stiffen from enhanced collagen fiber alignment and expansion of the cardiac fibroblast population, which was reversed by blocking cardiac fibroblast function with targeted genetic silencing of p38. This cardiac fibroblast- targeted intervention unexpectedly improved the primary cardiac myocyte defects in contractile function and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in myocyte contractile function and instead demonstrate cardiac fibroblasts play an unequivocal role in DCM outcomes. As an extension of this work we propose the overarching hypothesis that atypical p38-mediated fibroblast adaptations to DCM-linked sarcomere mutations are irreversible with myocyte-centric approaches, owing to the disproportionate expansion of sensitized and hyperresponsive Periostin+ fibroblasts during postnatal development that when left functionally enabled by myocyte-targeted therapies leave inherited DCM hearts vulnerable to heightened fibrosis. This hypothesis will be tested with the following aims: [Aim 1] Examine the developmental & molecular basis for adaptive cardiac fibroblast expansion in an inherited DCM mouse model; [Aim 2] Examine the effectiveness of myocyte versus fibroblast-targeted genetic interventions at various stages of DCM disease progression; and [Aim 3] Examine the generalizability of p38-dependent cardiac fibroblast response to inherited & acquired DCM. Outcomes from this work will start to resolve unknown fibroblast-based mechanisms that link primary myocyte defects with the DCM disease process and identify whether therapeutic interventions for DCM may require fibroblast-specific strategies to be effective.