Role of cholecystokinin receptor in hepatocellular cancer

胆囊收缩素受体在肝细胞癌中的作用

• 批准号: 10477465
• 负责人: Martha Gay
• 金额: $ 16.3万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477465
• 关键词: Address; Applications Grants; Biochemical; Biology; Body Weight decreased; Budgets; CRISPR/Cas technology; Cells; Cholecystokinin; Cholecystokinin B Receptor; Cholecystokinin Receptor; Choline; Cirrhosis; Collagen; Development; Development Plans; Diet; Dietary Fats; Engineering; Epidemic; Epigenetic Process; Ethionine; Fibroblasts; Fibrosis; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gastrins; Gastrointestinal tract structure; Goals; Growth; Hepatic; Hepatic Stellate Cell; Hepatocarcinogenesis; Hepatology; Histologic; Histology; Human; Immunologist; Immunology; In Vitro; Inflammation; Inflammatory; Knock-out; Knockout Mice; Lead; Ligands; Liver; Liver Fibrosis; Liver Stem Cell; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Manuscripts; Mediating; Mediator of activation protein; Mentors; Methodology; MicroRNAs; Modeling; Mus; Neoplasm Metastasis; Organoids; Pathway interactions; Patients; Penetration; Peptic Ulcer; Pharmaceutical Preparations; Physiological; Preparation; Prevention; Primary carcinoma of the liver cells; Proglumide; Proteins; Publications; RNA; Receptor Activation; Research; Research Personnel; Risk; Role; Scientist; System; Testing; Therapeutic Agents; TimeLine; Tissue Microarray; Tissues; Training; Transgenic Mice; Transgenic Organisms; United States; Vitamin E; Work; antagonist; cancer cell; cancer risk; carcinogenesis; career; career development; chemokine receptor; cytokine; dietary; effective therapy; epigenetic regulation; epigenomics; experience; gastrointestinal; graduate student; human tissue; in vivo; innovation; liver inflammation; liver injury; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; nutrition; overexpression; prevent; protein expression; receptor; receptor expression; response; saturated fat; stellate cell; stem cell population; stem cells; subcutaneous; symposium; transcriptome; transcriptome sequencing; tumor; tumor growth; undergraduate student

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.

项目总结/摘要 背景：胆囊收缩素受体（CCK受体）是一种G蛋白偶联受体， 胃肠道消化功能和胃肠道的生长。CCK受体成为 在胃肠癌中过表达，其中受体被配体CCK或胃泌素激活， 刺激癌症生长和转移。CCK受体也被描述为成纤维细胞。当 这些细胞被激活后，会产生胶原相关蛋白，导致与恶性肿瘤相关的纤维化 并且被认为阻碍治疗剂的渗透。 创新：我们最近发现，高饱和脂肪饮食诱导肝脏CCK- B的表达 受体在非酒精性脂肪性肝炎的鼠模型中的表达。CCK受体拮抗剂，丙谷胺， 逆转的炎症、纤维化和脂肪变性阻止了肝细胞癌的发展。 鼠NASH模型。 长期目标：在本研究中，我计划研究CCK受体如何介导 肝脏炎症和纤维化以及CCK受体在肝细胞癌中的作用。 研究目的：将进行体外研究，以分析CCK之间串扰的可能性 受体和趋化因子受体。CCK受体在星状细胞调节肝纤维化中的作用 在体外使用CRISPR技术选择性地敲除癌细胞CCK受体， 转基因小鼠被设计为没有CCK-B受体。最后，我们将探讨新的想法， 肝损伤和NASH是否诱导表达CCK-B受体的肝干细胞增殖， 这些干细胞是HCC的原因。 候选人的目标：了解胆囊收缩素受体在肝癌发展中的病理生理学， 进展本建议书将在经验丰富的导师团队的指导下完成，导师团队包括 有成就的肿瘤生物学家、免疫学家和肝癌研究人员。完成这些 目标，候选人将与她的导师，并不断审查研究目标出版， 解决候选人的出版记录和专业发展办公室遵循职业生涯 发展计划，采用各种方法，其中包括手稿 准备，项目管理遵守时间表，有效地管理预算，参加和 出席全国会议和部门研讨会，指导研究生和本科生 学生，准备申请材料。