The ASPIRE Path in Molecular Medicine

My thesis research focuses on the metabolic alterations occurring during the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in the liver and other metabolically active organs. Despite its increasing prevalence, there are no FDA-approved pharmacotherapies. Beyond its role in metabolic syndrome, steatosis is also common following liver transplants. During steatosis, calcium accumulates in the cytosol of hepatocytes, which can enter the mitochondria to activate mitochondrial enzymes. These accelerated metabolic rates fuel enhanced gluconeogenesis, resulting in increased reactive oxygen species generation leading to liver injury. Targeting calcium presents a challenge because it is a major signaling mediator throughout tissues, but NAFLD is a systemic disease, with metabolic effects in the heart, skeletal muscle, and brain. Hence, potential treatments may exacerbate extrahepatic injury. I model metabolic fluxes using isotopically labeled tracers to explore how activation of the enzyme SERCA affects metabolism of the liver, heart, brain, skeletal muscle, and adipose tissue, combined with tissue-specific functional tests. I employ two strategies for activating SERCA: systemic pharmacological activation and inhibiting isoform-specific negative regulation. Communication with clinicians will be central for translating my research and identifying new mechanisms to inform the development of NAFLD therapeutics and reduce its disease burden.