Serotonergic antidepressants as liver tumor preventives

血清素能抗抑郁药作为肝肿瘤的预防剂

• 批准号: 10055779
• 负责人: Kimberley Jane Evason
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-13 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055779
• 关键词: Ablation; American; Amitriptyline; Animal Model; Antidepressive Agents; CCL15 gene; Cancer cell line; Cell Line; Cell Survival; Chemicals; Cirrhosis; Clinical Research; Data; Diagnostic; Disease; Excision; Fatty Liver; Foundations; Gene Expression; Genes; Goals; Growth; HTR2A gene; Hepatitis C; Hepatocarcinogenesis; Hepatocyte; Human; Liver; Liver diseases; Liver neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Minority; Mission; Modeling; Molecular; Mus; Natural regeneration; Obesity Epidemic; Orthologous Gene; Paroxetine; Patients; Pharmaceutical Preparations; Prevention; Preventive; Primary carcinoma of the liver cells; Public Health; Reagent; Receptor Activation; Receptor Cell; Recurrence; Reporting; Research; Research Support; Retrospective Studies; Risk; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Antagonists; Signal Pathway; Signal Transduction; Steatohepatitis; Synapses; Testing; Tumor Burden; Veterans; Work; Zebrafish; base; cancer cell; cancer prevention; career; cell type; chronic liver disease; experience; high risk; improved; in vivo; knock-down; liver transplantation; novel therapeutics; prevent; programs; receptor; response; reuptake; serotonin receptor; tool; transcriptome sequencing; tumor; tumorigenesis; zebrafish development

PROJECT SUMMARY/ABSTRACT The number of Americans at risk for hepatocellular carcinoma (HCC) is increasing due to the growing obesity epidemic and its association with fatty liver disease, steatohepatitis, and cirrhosis. No medications have been shown to prevent HCC in high-risk patients with chronic liver disease. The long-term goal is to define mechanisms of hepatocarcinogenesis, providing a foundation for improved preventives, diagnostic tools, and treatments for HCC. The overall objective of this proposal is to identify cellular and molecular mechanisms by which serotonin promotes and antidepressants inhibit liver growth and tumor formation. The central hypothesis of this proposal is that 1) serotonin promotes liver growth and tumorigenesis by stimulating the serotonin receptor HTR2A on hepatocytes; and 2) serotonergic antidepressants inhibit liver growth and tumorigenesis by antagonism of HTR2A. The following specific aims are proposed to test this hypothesis: 1) Determine the cellular and molecular role of HTR2A in promoting liver tumor cell viability and liver growth; 2) Determine if amitriptyline suppresses liver growth and tumor formation via HTR2A; 3) Identify downstream genes that mediate amitriptyline’s effects on -catenin-driven liver growth and tumorigenesis and determine whether amitriptyline’s effects required activated -catenin. In Aim 1, the hypothesis that HTR2A mediates serotonin’s growth-promoting effects on HCC cells will be tested by measuring the effect of HTR2A knockdown on serotonin responsiveness of human liver cancer cell lines. In parallel, HTR2A orthologs will be knocked down in a zebrafish HCC model to determine the receptor and cell type(s) that mediate serotonin’s growth-promoting effects on hepatocytes in vivo. In Aim 2, the hypothesis that amitriptyline suppresses liver growth and tumor formation via inhibition of HTR2A will be tested using complementary approaches in human liver cancer cell lines and zebrafish as in Aim 1. In Aim 3, a prioritized list of genes, downregulated by amitriptyline treatment in mouse HCC, will be characterized for effects on liver growth and tumorigenesis and response to amitriptyline using zebrafish and mouse HCC models. The hypothesis that amitriptyline’s actions require activated -catenin will be tested. We expect the proposed studies to define how serotonin signaling and serotonergic antidepressants modulate liver growth and tumorigenesis. This research is significant because it will form the basis for identifying drugs to prevent liver cancer in high-risk patients, which could save thousands of lives each year.

项目概要/摘要 由于肥胖问题日益严重，面临肝细胞癌 (HCC) 风险的美国人数量不断增加 流行病及其与脂肪肝、脂肪性肝炎和肝硬化的关系尚未有药物治疗。 长期目标是确定可预防慢性肝病高危患者的肝癌。 肝癌发生机制，为改进预防措施、诊断工具和 该提案的总体目标是通过以下方式确定细胞和分子机制。 血清素促进肝脏生长和肿瘤形成，抗抑郁药则抑制肝脏生长和肿瘤形成。 该提议的要点是：1）血清素通过刺激血清素促进肝脏生长和肿瘤发生 肝细胞上的受体 HTR2A；2) 血清素能抗抑郁药通过以下方式抑制肝脏生长和肿瘤发生： HTR2A 的拮抗作用提出以下具体目标来检验该假设： 1) 确定 HTR2A 在促进肝肿瘤细胞活力和肝脏生长中的细胞和分子作用； 阿米替林通过 HTR2A 抑制肝脏生长和肿瘤形成；3) 识别下游基因 介导阿米替林对 β-连环蛋白驱动的肝脏生长和肿瘤发生的影响，并确定是否 阿米替林的作用需要激活的 β-连环蛋白。在目标 1 中，假设 HTR2A 介导血清素。 将通过测量 HTR2A 敲低对 HCC 细胞的生长促进作用来测试 与此同时，HTR2A 直系同源物将被抑制。 在斑马鱼 HCC 模型中确定介导血清素促进生长的受体和细胞类型 在目标 2 中，阿米替林抑制肝脏生长和肿瘤的假设。 通过抑制 HTR2A 肝脏的形成将在人类癌细胞中使用补充方法进行测试 品系和斑马鱼，如目标 1。在目标 3 中，基因优先列表，在阿米替林治疗中下调 小鼠 HCC，将表征对肝脏生长和肿瘤发生的影响以及对阿米替林的反应 使用斑马鱼和小鼠 HCC 模型假设阿米替林的作用需要激活的 β-连环蛋白。 我们期望拟议的研究能够定义血清素信号传导和血清素能如何。 抗抑郁药调节肝脏生长和肿瘤发生具有重要意义，因为它将形成肝脏生长和肿瘤发生。 确定预防高危患者肝癌的药物的基础，这可以挽救数千人的生命 每年。