Sharon DeMorrow, Ph.D.
Research Building 205, Central Texas Veterans Healthcare System
1901 South 1st Street
Temple, TX 76504
Education and Post-graduate Training
- 1994 - B.Sc (Hon I) Biochemistry; University of Queensland, Brisbane, Australia
- 1999 - Ph.D. Biochemistry; University of Queensland, Brisbane, Australia
- 2000 - Postdoctoral fellowship; Max Plank Institute for Psychiatry, Munich, Germany
- 2003 - Postdoctoral fellowship; Johannes Gutenberg University, Mainz, Germany
- 2005 - Postdoctoral fellowship; Scott & White Hospital, Temple, TX
- 1K01DK078532, 7/20/2007 – 6/30/2012 - NIH/NIDDK Endocannabinoid Regulation of Cholangiocarcinoma cell growth
- 1R03DK088012-01, 06/01/2010-05/31/2012 - NIH/NIDDK The role of progranulin in cholangiocarcinoma growth
- RSC 118760, 7/01/2010-6/30/2014 - American Cancer Society; Biogenic amines regulate cholangiocarcinoma cell growth
- 5 R01 DK082435, 7/01/2010-6/30/2015 - NIH/NIDDK Dysregulated Hypothalamic-pituitary-adrenal Axis During Biliary Hyperplasia
My research broadly focuses on the factors controlling hyperplastic and neoplastic cholangiocyte proliferation. Cholangiocytes are the epithelial cells that line in the intra- and extra-hepatic bile ducts and that are responsible for the modification of ductal bile.; These cells are the target of cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis, and are characterized by cholangiocyte proliferation and/or loss. This class of liver disease represents the first major indicator for liver transplantation in children and the third major indicator in adults. The neoplastic transformation of cholangiocytes into the malignant counterpart gives rise to cholangiocarcinoma, which has very few effective treatment options and poor prognosis. Thus, factors that affect the hyperplastic and neoplastic cholangiocyte proliferation may lead to novel treatment paradigms.
Autocrine and paracrine factors regulating cholangiocarcinoma growth
- We have identified the biogenic amines serotonin and dopamine as autocrine and paracrine factors that regulates cholangiocarcinoma growth. Specifically, cholangiocarcinoma cells produce increased levels of these biogenic amines, which can be detected in the bile of cholangiocarcinoma patients. This increased production is due to the increased expression of the sythesis enzymes and a marked suppression of the degradation enzyme monoamine oxidase A (MAOA). We have shown that the expression of MAOA correlates with tumor progression and overall survival with patients exhibiting lower levels of MAOA exhibiting a higher incidence of metastasis and poorer prognosis. We are currently extending our studies to assess the effects of serotonin and dopamine on the tumor microenvironment.
- In addition, we have recently shown that cholangiocarcinoma also express high levels of the novel growth factor progranulin, which has subsequent growth promoting effects.; We are also assessing the effects of this growth factor on the tumor microenvironment.
- Significance of the research: Cholangiocarcinoma is a devastating cancer that exhibits poor prognosis and surgical resection is virtually the only measure for a curative treatment.; Other attempts, including radiotherapy and photodynamic therapy, to relieve biliary obstruction due to non-resectable tumors have been demonstrated successfully as an adjuvant therapy following surgery or as palliative therapy. We believe that by dissecting the autocrine and paracrine pathways that regulate cellular growth and migration, we will identify possible target genes for therapies designed to slow the rate of cholangiocarcinoma growth that may potentially be used as part of a battery of therapies used to combat this bile duct malignancy.
The neurological changes that occurs during acute and chronic liver disease
- We have shown that during cholestatic liver disease, the hypothalamic-pituitary-adrenal axis is suppressed leading to decreased circulating glucocorticoid levels. We believe that the suppression of the HPA axis is probably as a result of increased circulating bile acids observed during liver damage. These bile acids cause a leakiness to the blood-brain-barrier and then enter the brain to bring about the neurological changes observed. This has opened up a very novel field of research in which bile acids should be viewed as neuroendocrine hormones rather than mere detergents that aid in fat digestion. We are exploring the implications of bile acid signaling in the brain on models of hepatic encephalopathy as well as in other neurological disorders.
- In a related project, hepatic encephalopathy is a serious neurological complication of liver failure thought to result from the accumulation of toxic substances in the blood stream. Associated with the cognitive deficits of hepatic encephalopathy is cerebral edema and astrocyte swelling in the cerebral cortex. Currently, our understanding of the events leading to hepatic encephalopathy is quite limited. The sonic hedgehog (Shh) pathway is upregulated during liver damage and Shh-positive microparticles have been found in the blood stream and are thought to regulate vascular permeability in an endocrine manner. Using a mouse model of hepatic encephalopathy, we have shown that the downstream effectors of hedgehog signaling, Gli1 and Gli2, are upregulated in the brain regions affected by hepatic encephalopathy but not in unaffected brain regions. Furthermore we have shown that transforming growth factor b (TGFb) is also released into the serum and may activate Gli1 and Gli2 independently of Shh. Our hypothesis is that during liver damage, this upregulation of Shh expression and release in the form of microparticles, leads to an increase in vascular permeability of the blood brain barrier, thereby allowing hedgehog ligands and TGFb, access to the brain where they may regulate the pathological changes seen in hepatic encephalopathy. We are currently dissecting the molecular events leading to the activation of Gli1 in the brain and are making efforts to identify downstream targets of Gli1 activity.
- Significance of the research: Liver cirrhosis is a consequence of various acute and chronic liver diseases. Generally, liver damage from cirrhosis can be managed, but not reversed. Both of these conditions may ultimately result in the need for liver transplantation. Therefore, management of both acute and chronic liver diseases represents one of the major challenges for the US Healthcare system. One serious complication of both liver cirrhosis and acute liver failure is hepatic encephalopathy, a pathological state arising after liver disease that leads to neurological deficits. Gaining understanding into the mechanism underlying the neurological changes associated with liver diseases – from mild effects (eg suppression of the HPA axis) to severe changes (eg overt hepatic encephalopathy) can lead to therapeutics to help improve the outcome of patients with HE.
- G. Alpini, P. Invernizzi, E.Gaudio, J. Venter, S. Kopriva, F. Bernuzzi, P. Onori, A. Franchitto, M. Coufal, G.A. Frampton, D. Alvaro, S.P. Lee, M. Marzioni, A. Benedetti, S. DeMorrow*. (2008) Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth. Cancer Res. 2008 Nov 15;68(22):9184-93. PMID: 19010890 PMCID: PMC2593938.
- G Frampton, L. Huang, J. Ramirez, A Mohamad, S DeMorrow*. (2010) The biogenic amines serotonin and dopamine regulate cholangiocyte hyperplastic and neoplastic growth. World Journal of Gastrointestinal pathophysiology 1(2) 63-68. PMID: 21607143 PMCID: PMC3097942
- L. Huang, G Frampton, L, Liang, S DeMorrow*. (2010) Aberrant DNA methylation profile in cholangiocarcinoma. World Journal of Gastrointestinal pathophysiology 1(2) 23-29. PMID: 21607139 PMCID: PMC3097943
- M Coufal, P Invernizzi, F Bernuzzi, GA Frampton, D Alvaro, M Marzioni, G Battisti, A Benedetti, S DeMorrow*. (2010) Increased local dopamine secretion has growth promoting effects in cholangiocarcinoma. Int J Cancer;126(9):2112-22. PMID: 19795457 PMCID: PMC2830344
- G. Frampton, M. Coufal, H. Li, J. Ramirez, S. DeMorrow*. (2010) Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling. Exp Cell Res. 316(9):1465-78. PMID: 20347808 PMCID: PMC2872061
- G Frampton, E Lazcano, L. Huang, A Mohamad, S DeMorrow*. (2010) Resveratrol enhances the sensitivity of cholangiocarcinoma to chemotherapeutic agents. Lab Invest. 90(9):1325-38 PMID: 20458282 PMCID: PMC2921554
- L. Huang, M.A. Quinn, G.A. Frampton, L.E. Golden, S. DeMorrow*. (2011) Recent advances in the understanding of the role of the endocannabinoid system in liver diseases. Dig Liver Dis;43(3):188-93 PMID: 20934397, PMCID: PMC3033442
- L Huang, J. Ramirez, G. Frampton, L. Golden, M. Quinn, HY Pae, D Horvat, L. Liang, S. DeMorrow* (2011) Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor. Laboratory Investigation, 91(7):1007-17. PMID: 21464819
- M. Quinn, Y. Ueno, H. Pae, L. Huang, G. Frampton, C. Galindo, H. Francis, D. Horvat, M. McMillin, S. DeMorrow* (2011). Suppression of the HPA axis during extrahepatic biliary obstruction induces cholangiocyte proliferation. Am J Physiol Gastrointest Liver Physiol. In press
- G. Frampton, P. Invernizzi, F. Bernuzzi, H Pae, D Horvat, C. Galindo, M. Quinn, L. Huang, M. McMillin, L. Rimassa, S DeMorrow*. (2011) Interleukin-6- driven progranulin expression increases cholangiocarcinoma growth by an Akt dependent mechanism. Gut. In press.