University of Malta, Malta B.S.
University of Malta, Malta M.S.
Univeristy of Aberdeen, UK Ph.D.
Postdoctoral Fellow, NCI, NIH
- Pancreatitis is a necro-inflammatory disease with acute and chronic manifestations. Published and pilot data from our laboratory have established that parathyroid hormone-related protein (PTHrP) plays a key role in the pro-inflammatory and pro-fibrotic responses associated with pancreatitis. We have shown that PTHrP levels are elevated in a mouse model of cerulein-induced acute pancreatitis, and that inhibition of PTHrP expression/signaling attenuates the injurious effects of cerulein in isolated acinar and stellate cells. To further study the role of PTHrP in pancreatic inflammation and fibrosis, our laboratory has developed a mouse model with deletion of the Pthrp gene in acinar cells, the initial sites of injury in acute and chronic pancreatitis. Pthrp gene deletion in these cells suppressed histological damage (edema and necrosis), inflammation and fibrosis in two well-established models of chronic pancreatitis. Based on these findings, we propose that pancreatic injury results in activation of injurious pathways within the pancreas, with the PTHrP signaling pathway being one such pathway. We are now defining the molecular mechanisms by which PTHrP exerts its pro-inflammatory and pro-fibrotic effects following pancreatic injury, and directly investigating whether small molecule inhibitors of PTHrP signaling exert a protective effect after pancreatic injury.
- Epidemiological studies strongly support evidence that dietary components can exert protective effects. An inverse correlation exists between colorectal carcinoma (CRC) incidence and serum levels of 25-hydroxyvitamin D (25D). 1,25D decreases cell proliferation and induces cell differentiation and apoptosis. Vitamin D receptor (VDR) levels are decreased in the inflamed colon and in CRC; these effects are mediated via the transcription factors Snail1 and Snail2, and lead to failure of therapy with 1,25D analogs. We have shown that the flavonolignan silibinin reverses upregulation of Snail1 and Snail2 in the 1,25D-resistant human colon carcinoma cells HT-29. These silibinin effects are accompanied by increased VDR levels. While 1,25D had no significant effect on HT-29 cell proliferation and migration, co-treatment with silibinin restored 1,25D responsiveness. In addition, co-treatment with silibinin plus 1,25D decreased proliferation and migration at doses where silibinin alone had no effect. These findings demonstrate that this combination may present a novel approach for chemotherapeutic interventions to target CRC in conditions of chronic colonic inflammation. We will be pursuing these studies in an in vivo model.
- Bhatia, V., Kim, S.O.K., Aronson, J.F., Chao, C., Hellmich, M.R., and Falzon, M. Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis. Regulatory Peptides 175, 49-61, 2012.
- Bhatia V, Mula RV, and Falzon M. Parathyroid hormone-related protein regulates integrin α6 and β4 levels via transcriptional and post-translational pathways. Exp. Cell Research 319:1419-1430, 2013.
- Bhatia, V., Rastellini, C., Han, S., Aronson, JF, Greeley, GH, Jr., and Falzon, M. Acinar cell-specific knockout of the Pthrp gene decreases the pro-inflammatory and profibrotic response in pancreatitis. Amer. J. Physiol. Gastrointestinal Liver Physiol. 307:G533-G549, 2014.
- Rastellini, C., Han, S., Bhatia, V., Cao, Y., Liu, K., Gao, X., Ko, T.C., Greeley, G.H. Jr., and Falzon, M. Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin and PTHrP expression in mice. Amer. J. Physiol. Gastrointestinal Liver Physiol. 309:G554-565, 2015.
- Falzon, M.; Bhatia, V. Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis. Cancers 7:1091-1108, 2015.
- Bhatia, V., Cao, Y. Ko, T.C., and Falzon, M. PTHrP interacts with the TGF-β/BMP-2/Gremlin signaling pathway to regulate pro-inflammatory and pro-fibrotic mediators in pancreatic acinar and stellate cells. Pancreas, 2016 May-Jun;45(5):659-70.
- Bhatia, V., and Falzon, M. Restoration of the anti-proliferative and anti-migratory effects of 1,25-dihydroxyvitamin D by silibinin in vitamin D-resistant colon cancer cells. Cancer Letters 362:199-207, 2015.
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