The focus of the Dasarathy laboratory is to dissect the molecular mechanisms of skeletal muscle loss in disease. The group evaluates the metabolic and molecular perturbations in the skeletal muscle in chronic diseases including liver disease.
Muscle loss is consistently observed in patients with hepatocellular carcinoma and affects clinical outcomes. The group has identified hyperammonemia as a mediator of muscle loss in disease. One of the characteristic phenotypes of patients with malignancies is a progressive and severe loss of muscle mass that affects survival, quality of life and response to therapy. Hyperammonemia has been observed in a number of malignancies especially rapidly growing tumors. The group's ongoing studies have identified a unique cellular response to ammonia induced stress.
The group's studies also focus on determining the mitochondrial and bioenergetic dysfunction during hyperammonemia. Malignant cells have perturbations in ammonia metabolism but the cellular response to ammonia has not been identified. The group's integrated metabolic-molecular approach to determine mechanistic perturbations in malignancies is now being extended to dissecting the cellular response to the oncometabolite, 2 deoxyglutarate, on glioma tumor microenvironment.
In summary, the Dasarathy laboratory focuses on the consequences of chronic diseases including malignancies on perturbations in the skeletal muscle. These studies have broad clinical applications because they lay the foundation to develop novel, mechanism-based targeted therapies to restore protein homeostasis and molecular and metabolic perturbations in chronic diseases including malignancies.