Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease in Western
countries. ALD is associated with increased mortality due to a broad spectrum of hepatic pathologies ranging
from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and hepatocellular
carcinoma. Recent studies have drawn attention to other factors contributing to ALD, including alterations in
the vasculature, portal tract inflammation and peribiliary fibrosis, and ductular reaction (i.e., activation of the
neuroendocrine phenotype of cholangiocytes). However, very little information is known about the effects of
alcohol on biliary epithelial cells (i.e., cholangiocytes). Substance P (SP) is a neuropeptide secreted
predominantly from sensory neurons and is known to play a key role in neuroinflammation via the recruitment
and activation of immune cells. Previous studies have shown an upregulation of the SP/NK1R axis in
cholangiocytes in response to liver injury due to cholestasis and that SP regulates cholangiocyte proliferation
via cAMP/PKA signaling. SP has been shown to increase hepatic fibrosis via differential changes in
cholangiocytes and hepatic stellate cell (HSCs) senescence. However, the SP/NK1R axis's role in ALD has not
been explored. Based on novel preliminary data, the central hypothesis is that ALD-induced ductular reaction
triggers a neuroendocrine phenotype in cholangiocytes whereby secretion of SP stimulates hepatic steatosis
and fibrosis and increases infiltration and activation of immune cells occurs during the progression of ALD in
proposed. To address the central hypothesis, two specific aims are proposed: 1) determine the expression and
distribution of SP/NK1R axis during the progression of ALD in human samples and a mouse model of alcohol-
induced liver injury; and 2) determine the therapeutic potential of the knockdown and/or pharmacological
inhibition of the SP/NK1R axis in a mouse model of ALD and human ALD-derived liver organoids. The
expected outcome of this work is an understanding of the role of the SP/NK1 axis and downstream signaling
mechanisms in the pathogenesis of ALD. The successful completion of the proposed studies will have a
significant positive impact on the knowledge of factors regulating ductular reaction observed in ALD and lay the
groundwork for developing novel therapeutic approaches for ALD.