PROJECT SUMMARY/ABSTRACT Obesity is approaching an epidemic state in the United States and is strongly associated with a higher risk of heart failure with preserved ejection fraction (HFpEF), a major cause of morbidity and mortality in obese individuals. In the VA population, HFpEF accounts for approximately 7% of all mortalities, and its prevalence in the VA Healthcare system is expected to increase exponentially over the coming decade with the aging Veterans population. Despite significant advances in the management of heart failure with reduced ejection fraction, few advances have been made in the management of HFpEF which carries a dismal survival rate of 50% in two years after diagnosis. Therefore, HFpEF represents an unmet need in modern clinical practice. Obesity induces systemic inflammation contributing to HFpEF, however, the mechanisms responsible for this phenomenon are not fully understood. In fact, therapeutics that nonspecifically target inflammation failed in multiple HF trials, highlighting the knowledge gap in the field. We identified a critical role for the bioactive lipid lysophosphatidic acid (LPA) in cardiac-BM signaling, cardiac inflammation, and adverse cardiac remodeling. Our preliminary data and published reports demonstrate increased plasma levels of autotaxin (ATX) and LPA in obese patients and animal models of diet-induced obesity (DIO), related to the increased mRNA expression of ATX in adipocytes, which hydrolyzes lysophosphatidylcholine (LPC) into LPA. However, the role of ATX/LPA signaling in obesity- induced cardiac inflammation and HFpEF, as well as related therapeutic targets, have not been explored. This project is clinically relevant as targeting this pathway, using clinically available therapeutics, can improve the outcomes of millions of patients with HFpEF who have limited therapeutic options. Our long-term goal is to identify the immune mechanisms regulating pathological heart remodeling in obesity. Our central hypothesis is that LPA plays an important role in obesity-related cardiac inflammation and fibrosis and that inhibiting ATX/LPA signaling is therapeutically beneficial. We collected extensive pilot data using unbiased approaches, including mass cytometry (CyTOF) and RNA sequencing (RNAseq), to characterize the immune landscape during DIO-related pathological cardiac remodeling. This data highlights the critical role of ATX/LPA signaling and macrophages in obesity-induced HFpEF and support the following specific aims: 1) Aim 1. Identify the mechanistic role of ATX/LPA nexus in macrophage signaling during obesity-induced HFpEF, 2) Determine how adipose-derived ATX signaling mediates obesity-induced HFpEF, and 3) Investigate the association between LPA levels, heritable genetic variability in LPA metabolism, and the development of HFpEF in humans. These aims will be conducted by a team with extensive clinical, basic and translational research experience in studying heart/BM signaling, immunomodulation ...