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Aldons (Jake) Lusis is Professor of Microbiology, Human Genetics and Medicine at the University of California, Los Angeles. His lab studies naturally occurring genetic variations in mice and in humans to help understand interactions underlying complex cardiovascular and metabolic disorders. A major focus of the lab has been to integrate clinical traits with “intermediate" phenotypes obtained using high throughput technologies such as RNA sequencing, metabolomics, or proteomics, an approach known as "systems genetics". To facilitate this approach, they have developed a reference resource termed the Hybrid Mouse Diversity Panel (HMDP) that can be used to carry out whole-genome association mapping. Current research projects include atherosclerosis, heart failure, and fatty liver disease. The present lecture will focus on a poorly understood form of heart failure (HF) called HF with preserved ejection fraction, or HFpEF. I will discuss a novel liver-heart endocrine circuit that has an impact on HFpEF (Cao Y, Wang Y, Zhou Z, Pan C, Jiang L, Zhou Z, Meng Y, Charugundla S, Li T, Allayee H, Seldin MM, Lusis AJ.  (2022) Liver-heart crosstalk mediated by coagulation factor XI (F11) protects against heart failure.  Science 377:1399-1406).