Chronic liver disease and cirrhosis are a worldwide problem and the 12th leading cause of death in the U.S.
Liver cirrhosis is preceded by fibrosis, which is a reversible, wound-healing response characterized by the
synthesis of abnormal and excessive extracellular matrix by myofibroblasts. Liver myofibroblasts arise from
the differentiation of heterogeneous precursors, most notably hepatic stellate cells. Targeting myofibroblast
differentiation is a logical strategy to limit fibrosis and enhance recovery from liver disease. However, the
mechanisms that regulate myofibroblast differentiation are not completely understood, and currently there
are no anti-fibrotic drugs approved for use in the U.S. We recently discovered that myofibroblast
differentiation is increased by exogenous activation of the aryl hydrocarbon receptor (AhR). We will
mechanistically determine how exogenous and endogenous AhR signaling impacts myofibroblast
differentiation and liver fibrosis. We will test the hypothesis that AhR signaling is a regulator of myofibroblast
differentiation. We will determine how AhR signaling regulates myofibroblast differentiation. We will test the
possibility that a selective AhR modulator (SAhRM) holds promise for therapeutic use in suppressing
myofibroblast differentiation using whole transcriptome sequencing and multiplex assays. We will determine
how exogenous AhR activation enhances myofibroblast differentiation using well-established mouse models
of liver fibrosis. We will determine if TCDD directly or indirectly targets myofibroblast differentiation during
liver fibrosis using conditional AhR knockout mice in which the AhR is removed from either hepatic stellate
cells or from parenchymal hepatocytes. As Junior Investigator in the COBRE in Matrix Biology, I will work
with my scientific mentor to complete the aims and develop a grant proposal for future R01 funding.
For more information about Dr. Kristen Mitchell please click here.