Hill Lab
Research Focus
The Hill laboratory focuses on the metabolic underpinnings of cardiometabolic health and disease. This involves critical examinations of glycolysis, mitochondria, and biosynthetic pathways of metabolism and development of causal relationships between metabolic changes and (patho)physiology. In addition, we maintain a strong interest in developing new approaches for measuring and delineating the significance of changes in cellular metabolism as they relate to health and tissue remodeling. Our early studies helped to standardize metabolic profile assays that are now used widely for examining cellular energetics, and we have continuously increased our capabilities to examine both catabolic and anabolic metabolism using radioactive or stable isotope labeling techniques. We are applying these methods to examine how physiological stressors such as exercise and pathological stressors such as pressure overload or myocardial infarction influence cardiac metabolism. Current projects in the laboratory focus on how fibroblasts and fibroblast metabolism dictate cardiac repair after myocardial infarction; how cardiomyocyte metabolism and aging influence myocardial blood flow and the ability to exercise; and how metabolic channeling contributes to cardiac biology. Regarding nutrition, we are particularly interested in how diet and nutrition affect cardiac remodeling and have identified that dietary branched-chain amino acids have prominent effects on cardiac function and remodeling after myocardial infarction.
Cardiac Metabolism
A foundational research area of the laboratory is cardiac metabolism. The heart has an extremely high ATP demand, which is fulfilled primarily by oxidative phosphorylation and glycolysis. To support its energetic needs, the heart uses multiple substrates, which compete for catabolism. However, cardiac metabolism is not solely about energy; it is also required to maintain biosynthesis to uphold the structure and function of the heart and to provide signaling cues for (patho)physiological remodeling. Accordingly, our laboratory has focused on ancillary biosynthetic pathways of glucose metabolism and how changes in their activity influence the heart. Moreover, we are interested in understanding how metabolic changes caused by exercise influence physiological adaptation of the heart, and our recent studies begin to shed light on how cardiomyocyte metabolism regulates myocardial blood flow, which could have important implications for the ability to exercise and age gracefully (if there is such a thing!).
Fibroblast Biology and Tissue Repair
Fibroblasts are highly plastic cells that uphold the structural architecture of tissue by coordinating extracellular matrix (ECM) deposition and by transmitting chemico-physical signals. After tissue injury, fibroblasts differentiate to more specialized phenotypes that proliferate, communicate to other cell types, and promote ECM deposition and wound closure. In contexts of extensive damage, as occurs with myocardial infarction (MI), fibroblasts participate in cell-cell communication to influence inflammatory responses and deposit ECM to promote fibrous scar formation and prevent myocardial rupture. After scar formation, cardiac fibroblasts may also participate in pathophysiological remodeling by depositing excessive levels of ECM in otherwise non-injured regions, worsening myocardial compliance and function. Although fibroblasts leverage metabolism to achieve cell state transitions and promote ECM accretion, it remains unclear how metabolic remodeling occurs in fibroblasts and how unique metabolic steps or processes contribute to their fundamental properties. Accordingly, our research is focused on understanding how fibroblasts influence post-MI remodeling and how changes in metabolism influence fibroblast-mediated tissue repair.
Nutritional Regulation of Cardiometabolic Health
Nutrition and metabolism are tightly interlinked. Although our early studies focused on how diets high in saturated fat influence cardiovascular health, our recent studies focus on how other nutrients, such as branched-chain amino acids (BCAAs), regulate myocardial health and remodeling. We have found that a diet low in BCAAs improves cardiac function after myocardial infarction, which could have translational implications for improving recovery of patients after a heart attack. Furthermore, we are interested in how food supplements and contaminants affect cardiometabolic health and see the area of nutrition as being an impactful direction for future studies.
