The OVERALL OBJECTIVE of this renewal is to define the mechanisms, consequences and pathologic outcomes of cholangiocyte senescence in the syndrome of primary sclerosing cholangitis (PSC). While the cholangiocyte plays an integral role in the cholangiopathies, including PSC, how cholangiocyte signaling contributes to the initiation and progression of PSC is unknown. Recent evidence from our lab supported by this grant indicates that: (i) cholangiocytes express pathogen recognition receptors (PRRs) including toll-like receptors (TLRs); (ii) upon pathogen recognition, cholangiocytes are activated to initiate downstream signaling pathways involving Nuclear Factor Kappa B (NF?B), the p21 Ras isoform, Mitogen Activated Protein Kinase (MAPK) and post-transcriptional regulatory networks involving microRNAs (miRNA), including let-7i; (iii) cultured human cholangiocytes, in response to potentially injurious microbial molecules, develop a senescent phenotype with characteristics of stress-induced senescence; (iv) these senescent cholangiocytes transition to a senescence-associated secretory phenotype (SASP) characterized by excessive expression and release of proinflammatory mediators, including IL6 and IL8; and (v) liver tissue from patients with PSC exhibits an increased proportion of cholangiocytes with the senescent and SASP phenotype compared to normal and disease control tissue. Thus, our data support the original CENTRAL HYPOTHESIS that persistent exogenous insult induces TLR-dependent activation of Ras/MAPK promoting let-7i miRNA - dependent cholangiocyte senescence and SASP, a phenotype that contributes to the fibroinflammatory features of PSC. We will test this hypothesis by using novel in vitro biochemical and molecular techniques and in vivo animal models to dissect the mechanisms, consequences and pathologic outcomes of cholangiocyte senescence and SASP-induced secretion of proinflammatory mediators. Our proposal has three integrated SPECIFIC AIMS. FIRST, we will test the hypothesis that bacterial derived molecules in bile induce cholangiocyte senescence through Ras/MAPK activation and let-7i dependent epigenetic silencing of E2F- responsive cell cycle genes. SECOND, we will test the hypothesis that cholangiocytes transition to SASP by IL6- induced activation of C/EBP and promote paracrine-mediated cholangiocyte senescence and stellate cell activation via hypersecretion of proinflammatory mediators. FINALLY, we will test the hypothesis that, in the Mdr2-deficient mouse model of PSC, cholangiocyte senescence contributes to the characteristic inflammation while genetic reversal or inhibition of cholangiocyte senescence and SASP will ameliorate the biliary disease. Results from our innovative experiments will substantially clarify the signaling mechanisms by which potentially injurious biliary components cause cholangiocyte senescence and SASP in PSC, and will provide novel information that could impact our ability to slow progression of this incurable disease.
This application examines the mechanisms, consequences and pathologic outcomes of cholangiocyte senescence in the syndrome of primary sclerosing cholangitis (PSC), an uncommon, progressive liver disease for which no effective therapy exists except liver transplant. If successful, the results of our studies could lead to new and potentiall effective treatments.
| 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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