Serotonergic antidepressants as liver tumor preventives

血清素能抗抑郁药作为肝肿瘤的预防剂

基本信息

批准号：
10296656
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-13 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10296656
关键词：
Ablation American Amitriptyline Animal Model Antidepressive Agents CCL15 gene Cancer cell line Cell Line Cell Survival Chemicals Cirrhosis Clinical Research Data Disease Excision 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 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 antagonist base cancer cell cancer prevention career cell type chronic liver disease diagnostic tool experience fatty liver disease high risk improved in vivo knock-down liver cancer model liver transplantation novel therapeutics prevent programs receptor response reuptake serotonin receptor tool transcriptome sequencing tumor tumorigenesis zebrafish development

项目摘要

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.

项目摘要/摘要由于肥胖的增长，有肝细胞癌风险的美国人人数正在增加流行病及其与脂肪肝病，脂肪性肝炎和肝硬化的关联。没有药物显示可预防慢性肝病的高危患者中的HCC。长期目标是定义肝癌发生的机制，为改进的预防剂，诊断工具和 HCC治疗。该提案的总体目的是通过 5-羟色胺促进和抗抑郁药抑制肝脏生长和肿瘤的形成。中心假设该建议的是1）5-羟色胺通过刺激5-羟色胺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 Htr2a的对抗。提出了以下具体目的来检验以下假设：1）确定 Htr2a在促进肝肿瘤细胞活力和肝生长中的细胞和分子作用； 2）确定是否阿米替林通过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-catenin驱动的肝脏生长和肿瘤发生的影响，并确定是否是否阿米替林的效果需要激活-catenin。在AIM 1中，HTR2A介导5-羟色胺的假设通过测量HTR2A敲低对HTR2A的影响，将测试对HCC细胞的生长促进作用人肝癌细胞系的5-羟色胺反应性。同时，HTR2A直系同源物将被击倒在斑马鱼HCC模型中，以确定介导5-羟色胺生长促进的接收器和细胞类型对体内肝细胞的影响。在AIM 2中，阿米替林抑制肝脏生长和肿瘤的假设通过抑制HTR2A的形成将使用人肝癌细胞中的完整方法测试线条和斑马鱼如AIM 1。小鼠HCC的特征是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鼠标HCC模型。阿米替林的作用需要激活的-catenin的假设将进行测试。我们期望拟议的研究定义5-羟色胺信号传导和血清素能如何抗抑郁药调节肝生长和肿瘤发生。这项研究很重要，因为它将形成鉴定药物预防高危患者肝癌的基础，这可以挽救数千人生命每年。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.

DOI：
10.1073/pnas.2217425120
发表时间：
2023-05-30
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Ong, Athena Jessica S.;Bladen, Cerys E.;Tigani, Tara A.;Karamalakis, Anthony P.;Evason, Kimberley J.;Brown, Kristin K.;Cox, Andrew G.
通讯作者：
Cox, Andrew G.

Histologic features of allograft livers in patients treated for rejection before biopsy.

DOI：
10.1016/j.humpath.2023.02.005
发表时间：
2023-02
期刊：
Human pathology
影响因子：
3.3
作者：
N. Leonard;G. Hale;Katherine Boylan;Z. Ou;Chong-Jian Zhang;Robin D. Kim;S. Chandna;Z. Dong;K. Evason
通讯作者：
N. Leonard;G. Hale;Katherine Boylan;Z. Ou;Chong-Jian Zhang;Robin D. Kim;S. Chandna;Z. Dong;K. Evason

Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities.