Our long-term OBJECTIVES remain to apply the fundamental concepts and broad technologies of cell and molecular biology to understand the role of cholangiocytes, the epithelial cells lining intrahepatic bile ducts, in health and disease. We continue to focus on the interactions between cholangiocytes and Cryptosporidium parvum (C. parvum), an emerging pathogen causing intestinal and biliary cryptosporidiosis. Recent evidence from our lab indicates that: (i) the cellular expression and regulation of key receptors [Toll-like receptors (TLRs)] and specific intracellular signaling pathways (NF-kB activation) are involved in cholangiocyte C. parvum recognition and strategic defense;and (ii) endogenous microRNA (miRNA)-mediated post- transcriptional gene regulation is involved in cholangiocyte defense responses to C. parvum infection. Thus, we will test the CENTRAL HYPOTHESIS that C. parvum-cholangiocyte interactions activate host-cell TLR/NF-kB signaling cascades initiating cholangiocyte defense responses including upregulation of both TLRs and anti-microbial peptides (defensins) through both transcriptional and post-transcriptional endogenous miRNA-mediated) regulatory pathways. In our three integrated SPECIFIC AIMS, we will test the hypotheses that: (i) cholangiocyte TLRs recognize C. parvum and modulate NF-kB activation resulting in upregulation of anti-microbial peptides (human beta-defensins [HBDs]) and TLRs through NF-kB mediated transcriptional regulation;(ii) miRNA-mediated post-transcriptional repression of TLR expression normally exists in cholangiocytes, is regulated by TLR/NF-kB signals, and is involved in C. parvum-induced upregulation of TLRs;and (iii) expression of TLRs and HBDs in cholangiocytes are required for eradication of C. parvum infection in the biliary tract in in vitro and in vivo experimental models. Innovative aspects of our program include: novel methodologies [small-interfering RNAs (siRNAs)], animal models (biliary cryptosporidiosis in wild type, TLR and MyD88 knock out mice), and new concepts (miRNA-mediated gene regulation in cholangiocyte defense). Thus, the experiments will define the molecular mechanisms by which C. parvum-cholangiocyte interactions trigger host epithelial defense, with an emphasis on the role of miRNA- mediated post-transcriptional regulation in TLR-associated defense, a NEW CONCEPT that may have important generalizability to both innate and adaptive immunity in health and disease.
| Guicciardi, Maria Eugenia; Trussoni, Christy E; Krishnan, Anuradha et al. (2018) Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol 69:676-686 |
| Moncsek, Anja; Al-Suraih, Mohammed S; Trussoni, Christy E et al. (2018) Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2-/- ) mice. Hepatology 67:247-259 |
| Cheung, Angela C; Lorenzo Pisarello, Maria J; LaRusso, Nicholas F (2018) Pathobiology of biliary epithelia. Biochim Biophys Acta Mol Basis Dis 1864:1220-1231 |
| Cheung, Angela C; LaRusso, Nicholas F; Gores, Gregory J et al. (2017) Epigenetics in the Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. Semin Liver Dis 37:159-174 |
| Loarca, Lorena; De Assuncao, Thiago M; Jalan-Sakrikar, Nidhi et al. (2017) Development and characterization of cholangioids from normal and diseased human cholangiocytes as an in vitro model to study primary sclerosing cholangitis. Lab Invest 97:1385-1396 |
| Cheung, Angela C; Lazaridis, Konstantinos N; LaRusso, Nicholas F et al. (2017) Emerging pharmacologic therapies for primary sclerosing cholangitis. Curr Opin Gastroenterol 33:149-157 |
| O'Hara, Steven P; Splinter, Patrick L; Trussoni, Christy E et al. (2017) ETS Proto-oncogene 1 Transcriptionally Up-regulates the Cholangiocyte Senescence-associated Protein Cyclin-dependent Kinase Inhibitor 2A. J Biol Chem 292:4833-4846 |
| Gradilone, Sergio A; Pisarello, Maria J Lorenzo; LaRusso, Nicholas F (2017) Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma. Curr Drug Targets 18:958-963 |
| O'Hara, Steven P; La Russo, Nicholas F (2017) Cellular senescence, neuropeptides and hepatic fibrosis: Additional insights into increasing complexity. Hepatology 66:318-320 |
| Lazaridis, Konstantinos N; LaRusso, Nicholas F (2016) Primary Sclerosing Cholangitis. N Engl J Med 375:2501-2502 |
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