Project 2: Pathophysiology of Cholangiocyte Response to Injury
Cholangiocytes are periodically exposed to pathogen-derived toxins, such as lipopolysaccharide, or colonized by pathogenic microorganisms, such as Cryptosporidium. In this project, the Cholangiopathies lab focuses on the molecular mechanisms and functional consequences of microbe-induced signaling cascades culminating in a proinflammatory response by cholangiocytes.
More specifically, the Cholangiopathies lab studies microbe recognition-dependent activation of the inflammation-associated TLR-signaling axis, as well as implications of this on the regulated expression of microRNAs, small RNA molecules that regulate gene expression. Dr. LaRusso's research team proposes that this signaling pathway requires cholangiocyte TLRs, is enhanced in the absence of the multidrug-resistant 2 gene, and promotes cholangiocyte inflammatory responses, ultimately leading to fibrosis, or scarring of the bile ducts.
The long-term objective and specific aim of this project is to test the central hypothesis that C. parvum-cholangiocyte interactions activate host-cell TLR/NF-kΒ signaling cascades, initiating cholangiocyte defense responses including upregulation of both TLRs and antimicrobial peptides (defensins) through both transcriptional and post-transcriptional (endogenous miRNA-mediated) gene regulation.
The specific aims are to test three hypotheses:
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