Growth differentiation factor-15 (GDF15) as a novel myocardial hormone in heart failure

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Dilated cardiomyopathy (DCM) is a highly prevalent condition characterized by progressive cardiac dysfunction and interstitial cardiac fibrosis that leads to congestive heart failure (HF) and premature death. As HF progresses, some individuals will develop cardiac cachexia, which limits quality of life, reduces functional capacity, and confers an increased risk of death. Despite this, the molecular mechanisms that underlie cardiac cachexia are completely unknown. This knowledge gap prevents adequate treatment for a complication that may affect as many as 1,000,000 Americans. Delineating the molecular pathways driving cachexia would likely yield clinically actionable evidence that could impact HF care. The present proposal will address this knowledge gap. Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that can be produced by most organs secondary to a variety of stressors. GDF15 is an exquisitely sensitive biomarker that predicts new-onset cardiovascular events and death in healthy individuals and is highly prognostic in individuals with a wide range of chronic diseases, including HF. Despite this, the biologic function of GDF15 in the heart and in those with HF remains unknown. Recent evidence from animal models and the cancer literature has revealed that GDF15 acts via a very specific receptor, glial cell-derived neurotrophic factor receptor α-like (GFRAL), that is only expressed in the area postrema and nucleus tractus solitarius of the brainstem. In this context, GDF15 suppresses food intake, thus modulating systemic metabolism and reducing food intake. Under stress conditions (i.e., toxin ingestion, as with chemotherapy), this produces an aversive/anorexic response. But, when left unchecked (as when chronically overexpressed}, GDF15 triggers a catabolic-anabolic imbalance that results in cachexia. Evidence also suggests that GDF15 acts in a GFRAL-independent fashion via as-yet undiscovered mechanisms to elicit other responses including immunomodulation, suppression of fibrosis and altered cell cycling. Review of large transcriptomic datasets in the NCBl's GEO repository, including the Pl's earlier transcriptomic work in a genetic model of DCM, reveals that Gdf15 is substantially upregulated in a wide variety of HF models. This exploratory proposal will use genetic mouse models of GDF15 and GFRAL knock-out to study the role of the GDF15-GFRAL axis in cardiac cachexia and in DCM progression. Through detailed phenotyping, basic molecular methods, RNA sequencing and a small clinical pilot study in advanced HF patients, this proposal will lay the foundation for future research on the role of GDF15 in HF and cardiac cachexia. Our proposal is highly innovative and uses robust, unbiased methods to address important questions of great significance to the NHLBI. Our collaborative group brings synergistic expertise on cardiovascular disease models, body composition analysis, clinical research, and next-generation sequencing that will enhance the execution of this proposal. Ultimately, we expect our results will inform new diagnostic and therapeutic strategies for HF, thus targeting a tremendous unmet need in clinical cardiology.