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Sharon DeMorrow, Ph.D

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Assistant Professor
Department of Internal Medicine

2401 South 31st Street
Temple, Texas 76508
Phone: 254-724-6240
Fax: 254-724-8070
Email: demorrow@medicine.tamhsc .edu

Education and Post-Graduate Training

B.Sc (Hon I) Biochemistry, University of Queensland, Brisbane, Australia (1994)

Ph.D Biochemistry, University of Queensland, Brisbane, Australia (1999)

Research Interests

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.

Specifically, my research projects include:

Cholangiocarcinoma

1.    Endocannabinoid Regulation of Cholangiocarcinoma Cell Growth
This research project focuses on the opposing modulatory actions of the endocannabinoids, anandamide and 2-arachidonyl glycerol, on cholangiocarcinoma cell growth.  Endocannabinoids are the endogenous molecules that are structurally related to the active component of marijuana, THC. Modulation of the endocannabinoid system has been suggested as a potential target for the treatment of a number of cancers. We have novel preliminary evidence indicating that anandamide exerts antiproliferative effects, whereas 2-arachidonyl glycerol has growth promoting effects on cholangiocarcinoma cell growth. These opposing actions appear to be independent of any known cannabinoid receptor and is via the specific interactions and subsequent effects of the endocannabinoids on the lipid raft structures of the plasma membrane. In addition, a differential activation of Notch I and Notch 2 by anandamide and 2-arachidonyl glycerol respectively has been observed. Thus, the hypothesis is that the activation of Notch 1 signaling pathways are responsible for AEA-mediated antiproliferative effects, while Notch 2 signaling pathways are responsible for 2-AG growth promoting effects on cholangiocarcinoma cell growth.

2.    Biogenic amines regulate cholangiocarcinoma cell growth
Serotonin, dopamine, norepinephrine, epinephrine, and histamine are often collectively referred to as “biogenic amines”.  These agents play key roles in neurotransmission and other signaling functions.  We have preliminary data showing the increased production and secretion of serotonin and dopamine from cholangiocarcinoma cells and that increased serotonin and dopamine production results in the stimulation of cholangiocarcinoma cell growth and facilitates the activity of EGF (a known modulatory growth factor in the etiology of cholangiocarcinoma) on cell growth and matrix metalloproteinase-2 and -9 expression (genes responsible for the invasive properties of tumor cells).  Thus our hypothesis is that during the neoplastic transformation of cholangiocytes, the machinery responsible for the synthesis and degradation of these biogenic amines are dysregulated and that this contributes to the malignant progression of cholangiocarcinoma.

Cholestatic liver diseases

1.    The role of the HPA axis in cholestatic liver diseases
Cholestatic patients demonstrate clinical features suggestive of adrenal insufficiency such as hypovolemia and renal failure.  In the bile duct-ligated (BDL) model of cholestasis, there is a suppression of hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stress. The mechanism by which the HPA axis suppression occurs is poorly understood.  This project has three parallel aims:

    a.    What part of the HPA axis is suppressed in cholestatic liver diseases?
We will use an animal model of cholestasis (bile duct ligation) to determine the effects of extrahepatic biliary obstruction on the various levels of the HPA axis.  We have preliminary data showing that serum corticosterone levels are dramatically reduced after BDL.  We will assess whether steroidogenesis is suppressed at the level of the production and release of glucocorticoids from the adrenal glands, or whether the signal upstream from the pituitary (ACTH levels) or hypothalamus (CRH or AVP levels) are dysregulated.  An alternative explanation may be that there is a signal molecule that activates the negative feedback loop originating in the hippocampus that suppresses the HPA axis.  We will also assess if the suppression of the HPA axis and subsequent decrease in circulating glucocorticoids is responsible for the cholangiocyte proliferation observed after BDL.  Suppression of glucocorticoids will be achieved by adrenalectomizing rats and assessing biliary outgrowth.

    b.    Mechanism of HPA axis downregulation – effects of serum bile acids
A key feature of many cholestatic liver diseases is an increased serum bile acid concentration. The consequences of bile acids in the serum are unknown. Some bile acids have the ability to activate glucocorticoid receptors (GR), which are important in the regulation of the HPA axis.  Most of the key components of the HPA axis are protected by the blood brain barrier.  However, because of the detergent properties of bile acids, it is conceivable that increased serum bile acids can disrupt the blood brain barrier.  We will determine this in an in vitro model of blood brain barrier permeability and confirm our findings in vivo.  We then wish to determine the effects of the serum bile acids on the various components of the HPA axis similar to what is outlined above

    c.    Reactivation of the HPA axis by the central administration of corticotropin releasing hormone (CRH) reverses cholangiocyte proliferation in experimental cholestasis
Intracerebroventricular (icv) administration of CRH has been shown to activate the HPA axis resulting in increased circulating glucocorticoid levels.  We will use this feature to re-activate the suppressed HPA axis and bring the circulating glucocorticoid levels back to normal levels and determine the effects on biliary outgrowth and cholestasis.

Selected Publications

Fava G, Marucci L, Glaser S, Francis H, DeMorrow S, Reichenbach R, Benedetti A, Alvaro D, Venter J, Meininger C, Patel T, Taffetani S, Marzioni M, Summers R, and Alpini G. (2005)  Gamma-aminobutyric acid inhibits cholangiocarcinoma growth by cAMP-dependent regulation of the PKA/ERK1/2 pathway.  Cancer Research. 65(24): 11437-46

Glaser S, Alvaro D, Francis H, Ueno Y, DeMorrow S, Marucci L, Benedetti A, Marzioni M, Mancino MG, Phinizy JL, Reichenbach R, Fava G, Summers R, Venter J, and Alpini G. (2006)  Beta 1 and beta 2 adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt.  Am J Physiol. .290(4): G813-26

Glaser S, Francis H, DeMorrow S, Fava G, Marzioni M, LeSage G, Venter J, and Alpini G. Heterogeneity of the Intrahepatic Biliary Epithelium.  World J Gastroenterology 12(22):3523-3536, 2006.

DeMorrow S, Glaser S,  Francis H, Venter J, Vaculin B, Green B, and Alpini G. Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of death receptor into lipid rafts (2007).  J. Biol. Chem 282(17); 13098-13113.

Glaser S, Ueno Y, DeMorrow S, Chiasson V, Katki K, Venter J, Francis H, Dickerson I, DiPette DJ, Supowit S, and Alpini G. Knockout of a-calcitonin gene-related peptide prevents growth of cholangiocytes induced by extrahepatic bile duct obstruction.  2007 Lab. Invest 87(9): 914-26.

Francis H, LeSage G, DeMorrow S, Alvaro D, Ueno Y, Venter J, Glaser S, Marucci L, Benedetti A, Mancino MG, and Alpini G.  The a-2 adrenergic receptor agonist, UK 14,304, inhibits secretin-stimulated ductal secretion by impairing activation of the cAMP system. Am J Physiol Cell Physiol, 2007  293(4); C1252-62

DeMorrow S, Francis H, Venter J, Vaculin S, Vaculin B, Stutes M, Tran S, Wise C, Alpini G, Glaser S.  Nervous modulation of ductal secretion and cholangiocyte hyperplasia. In Pathophysiology of the biliary epithelium (DeMorrow, Marzioni, Fava, Glaser and Alpini eds).  Research Signpost In press

Stutes M, Tran S, DeMorrow S.  Genetic and epigenetic changes associated with cholangiocarcinoma: from DNA methylation to microRNAs. World Journal of Gastroenterology (2007) 13(48) 6465-9

DeMorrow S, Francis H, Alpini G.  Biogenic amine actions on cholangiocyte function Experimental Biology and Medicine (2007). 232: 1005-1013

X. Xia*, DeMorrow S,* Marzioni M, Fava G, Francis H, Alpini G, Glaser S, LeSage G.  Cholangiocyte Injury and ductopenic syndromes.  2007 27(4) 401-412 (* authors contributed equally).

DeMorrow S, Francis H, Gaudio E, Ueno Y, Venter J, Onori P, Franchitto A, Vaculin B, Vaculin S, and Alpini G. Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation. Am J Physiol. 2008 294(2) G506-19.