Project Summary/ Abstract Background: The cholecystokinin (CCK) receptor is a G-protein coupled receptor that regulates physiologic gastrointestinal digestive functions and growth of the gastrointestinal tract. CCK receptors become overexpressed in gastrointestinal cancers where receptor activation by the ligands, CCK on or gastrin, stimulate cancer growth and metastases. CCK receptors have also been described as fibroblasts. When activated, these cells produce collagen-associated proteins that lead to fibrosis associated with malignancies and are thought to impede the penetration of therapeutic agents. Innovation: We recently showed that a diet high in saturated fat induces the expression of hepatic CCK- B receptors in a murine model of nonalcoholic steatohepatitis. The CCK receptor antagonist, proglumide, reversed inflammation, fibrosis, and steatosis prevented the development of hepatocellular carcinoma in the murine NASH model. Long-term objectives: In this proposal, I plan to investigate the mechanisms of how CCK receptors mediate hepatic inflammation and fibrosis and the role of CCK receptors in hepatocellular cancer. Research Aims: In vitro studies will be performed to analyze the potential of cross-talk between CCK receptors and chemokine receptors. The role of CCK receptors in regulating hepatic fibrosis in stellate cells will be carried out in vitro using CRISPR technology to selectively knockout cancer cell CCK receptors and in vivo with transgenic mice engineered to be null in the CCK-B receptor. Lastly, we will examine the novel idea of whether liver injury and NASH induce proliferation of hepatic stem cells that express CCK-B receptors and these stem cells are responsible for HCC. Candidate's Goals: Are to understand the pathophysiology of CCK receptors in liver cancer development and progression. This proposal will be completed under the guidance of an experienced mentor team that includes accomplished tumor biologists, immunologists, and hepatology cancer researchers. To accomplish these goals, the candidate will work with her mentors and constantly review research objectives for publication to address candidate’s publication record and the Professional Development Office to follow a career development plan by incorporating diverse methodologies for advancement, which includes manuscript preparation, project management adhering to timelines, effectively managing a budget, attending and presenting at national conferences and departmental seminars, mentoring graduate and undergraduate students, and preparing application materials.

Project Narrative The overall purpose of this project is to understand the mechanism by which the cholecystokinin (CCK) B- receptor is activated in liver injury and NASH and how this activation increases the risk for hepatocellular cancer (HCC). Epigenetic regulation of the CCK receptor will be studied and cross-talk with chemokine receptors. Several murine models of liver injury and a transgenic CCK-BR-knockout mouse model will be used to investigate whether stem cells or liver progenitor cells express the CCK-BR and if a CCK-receptor antagonist can decrease the risk of HCC.