? This application describes a comprehensive research program designed to develop Dr. DeMorrow into an independent research scientist. Through a structured program of seminars, conferences and workshops throughout the duration of the K01 award, she will acquire the necessary background knowledge and analytical skills to achieve this goal. Development of grantsmanship is also emphasized, beginning with applications for intramural funds, graduating to applications for funding from the Veterans Affairs Administration and culminating in an R01 submission to the NIH in the third year of this award. The research plan focuses on the opposing modulatory actions of the endocannabinoids, anadamide [sic] and 2-arachidonyl glycerol, on cholangiocarcinoma cell growth. This devastating cancer has very limited treatment options and very poor prognosis, hence the development of novel therapeutic strategies is crucial to improve the clinical outcomes of this disease. Modulation of the endocannabinoid system has been suggested as a potential target for the treatment of a number of cancers. Dr DeMorrow presents 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 the applicant proposes that it 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 1 and Notch 2 by anandamide and 2-arachidonyl glycerol respectively has been observed. Thus, the applicant hypothesizes 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. To address this hypothesis, the applicant proposes 3 sequential specific aims: (1) to further define the differential effects of endocannabinoids on cholangiocarcinoma growth via cannabinoid receptor-independent, lipid raft mediated pathways; (2) to demonstrate that the differential regulation of cholangiocarcinoma growth by endocannabinoids requires Notch signal transduction pathways, and (3) to show that the differential activation of the Notch signaling pathways by endocannabinoids is dependent upon lipid rafts. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
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Scott and White Memorial Hospital
United States
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McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew et al. (2016) Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure. Am J Pathol 186:312-23
McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew et al. (2015) Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling. Mol Endocrinol 29:1720-30
McMillin, Matthew A; Frampton, Gabriel A; Seiwell, Andrew P et al. (2015) TGF?1 exacerbates blood-brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5. Lab Invest 95:903-13
Huang, Li; Chen, Wei; Liang, Peiwen et al. (2015) Serum CYFRA 21-1 in Biliary Tract Cancers: A Reliable Biomarker for Gallbladder Carcinoma and Intrahepatic Cholangiocarcinoma. Dig Dis Sci 60:1273-83
Meng, Fanyin; DeMorrow, Sharon; Venter, Julie et al. (2014) Overexpression of membrane metalloendopeptidase inhibits substance P stimulation of cholangiocarcinoma growth. Am J Physiol Gastrointest Liver Physiol 306:G759-68
Quinn, Matthew; McMillin, Matthew; Galindo, Cheryl et al. (2014) Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms. Dig Liver Dis 46:527-34
McMillin, Matthew; Frampton, Gabriel; Thompson, Michelle et al. (2014) Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline. J Neuroinflammation 11:121
McMillin, Matthew; Galindo, Cheryl; Pae, Hae Yong et al. (2014) Gli1 activation and protection against hepatic encephalopathy is suppressed by circulating transforming growth factor ?1 in mice. J Hepatol 61:1260-6
Renzi, Anastasia; DeMorrow, Sharon; Onori, Paolo et al. (2013) Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats. Hepatology 57:1130-41
Demorrow, Sharon (2013) Progranulin: a novel regulator of gastrointestinal cancer progression. Transl Gastrointest Cancer 2:145-151

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