Thorp Project Summary Abstract Diastolic dysfunction (DD) and Heart failure with Preserved Ejection Fraction (HFpEF) are significant and hetetogenous causes of morbidity and mortality with few effective therapeutic strategies. Increased understanding of HFpEF has been earmarked as a NIH research priority. Two risk factors, fat and hypertension, are commonly found in cardiometabolic HFpEF patients, and both independently associate with inflammation and DD. The extent of inflammation is a critical determinant of the degree of cardiac fibrosis and myocardial stress that likely contributes to impaired cardiac performance. As such, the resolution of inflmammation has the potential to ameliorate myocardial pathophysiology. In this context, inflammatory immunometabolic signaling has been linked with to the progression of disease, yet little is known with respect to how immune metabolism regulates DD. This is particuarly true for myeloid cells and especially the macrophage, in which immuonometabolic contriubtions to DD are either unknown or vague. Our preliminary data point to signifcant mitochondrial stress in macrophages during DD. This is an opportunity to combine improved basic understanding of basic cellular mechanisms with the revealing on potential new metabolic therapeutic targets. In our first experimental Aim, we will test the causal associations of myeloid lipid and mitochondrial metabolic pathways during experimental DD. Aim II will elucidate cell-intrinsic immunometabolic macrophage signaling networks that regulate pathways of inflammatory acceleration during DD-associated pathology. Aim III will test the therapeutic proof of principle and clinical relevance of myeloid cell metabolism during DD. Our Aims will leverage newly generated and cutting-edge experimental tools and approaches. Taken together, these studies will provide new insight into the underlying inflammatory mechanisms and therapeutic immune targets of DD and immunometabolic signaling.