Matrix in pre-cirrhotic HCC

肝硬化前 HCC 的基质

基本信息

批准号：
10578389
负责人：
Natalie J. Torok
金额：
$ 57.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578389
关键词：
3-Dimensional Acceleration Address Advanced Glycosylation End Products Affect Amino Acids Animal Model Architecture Behavior Cells Cirrhosis Clinical Collagen Data Deposition Diet Disease Progression Down-Regulation Elasticity Embryo Environment Epidemic Exhibits Future Hepatocyte Human Hydrogels Incidence Injections Injury Invaded Lead Link Liver Malignant Neoplasms Mediating Modeling Mus Neoplasm Metastasis Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pathway interactions Patients Phenotype Prevalence Primary carcinoma of the liver cells Production Proliferating Property Proteoglycan Pyridoxamine Relaxation Risk Factors Signal Transduction Stress System Techniques Testing Therapeutic Time Tissues Tumor Burden Viscosity Work beta catenin cancer cell carcinogenicity cell behavior cell motility cell transformation crosslink diabetic glycemic control improved in vitro Model in vivo in vivo Model inhibitor liver cancer model liver injury migration mutant nonalcoholic steatohepatitis novel permissiveness receptor receptor for advanced glycation endproducts response sex tensin three-dimensional modeling transcriptome sequencing translational study tumor viscoelasticity

项目摘要

Project Summary/Abstract Non-alcoholic steatohepatitis (NASH) is a major cause of HCC. It is clinically recognized that HCC in NASH often arises at a pre-cirrhotic stage, however the pathomechanism of HCC in non-cirrhotic livers is not well understood. As T2DM with poor glycemic control is an independent risk factor for HCC it is plausible that there are distinct pathways that create a pro- carcinogenic niche in non-cirrhotic T2DM/NASH. We showed that the accumulation of advanced glycation end products (AGEs) in patients with T2DM/NASH and in an animal model are key to necroinflammation and oxidative liver injury. Downregulation of the AGE clearance receptor AGER1 accelerated AGE deposition, and correcting AGER1 in vivo improved NASH. To study how high AGE environment creates permissive conditions for transformed cells, we modulated diet/AGE content prior to hydrodynamic injection of hMET/mutant β-catenin: 1) High AGE background induced an earlier and more invasive HCC, 2) AGE accumulation was linked to significant changes in matrix dynamics-with an increase in energy dissipation or loss and faster stress relaxation in response to a deformation - in an AGE and receptor for AGEs (RAGE)-dependent manner, 3) Inhibiting AGE production reversed changes in matrix viscoelasticity in vivo and lowered tumor burden. We will test the hypothesis that in non- cirrhotic T2DM/NASH accumulation of AGEs contribute to an increase in matrix viscoelasticity and matricellular changes creating a pro-invasive environment. Aim 1: We propose to investigate the link between diet/AGE content, matrix viscoelasticity, sex and HCC phenotypes and outcomes in a novel HCC model. In particular we will focus on how AGE-mediated collagen crosslinks on specific amino acids can alter intermolecular recognition and interaction with proteoglycans thereby affecting matrix dynamics. Aim 2: We will dissect the effects of RAGE and AGER1 signals and AGE accumulation on matrix viscoelastic parameters and HCC phenotypes. In Aim 3 we propose to develop a 3D hydrogel system with tunable viscoelasticity and the impact of AGEs-modified matrix on cell behavior will be studied. Based on the RNAseq data we will focus on the pathomechanism of how viscoelastic changes are sensed by cells, and the key matricellular signals that confer invasive and migratory properties. These studies will demonstrate the impact of AGEs on the liver matrix in non-cirrhotic NASH and outline the pathomechanism for a pro-invasive environment. Defining the key matricellular signals that drive invasion will enable us to pursue translational studied in the future.

项目概要/摘要临床上公认，非酒精性脂肪性肝炎（NASH）是肝癌的主要原因。 NASH 中的 HCC 通常出现在肝硬化前期，然而 HCC 的病理机制非肝硬化肝脏尚不十分清楚，因为血糖控制不佳的 T2DM 是一种常见疾病。作为 HCC 的独立危险因素，有可能存在不同的途径来产生 HCC 的独立危险因素。我们发现非肝硬化 T2DM/NASH 中的致癌生态位。 T2DM/NASH 患者和动物模型中的晚期糖基化终末产物 (AGE) 是坏死性炎症和氧化性肝损伤的关键。受体AGER1加速AGE沉积，纠正体内AGER1可改善NASH。为了研究高 AGE 环境如何为转化细胞创造有利条件，我们在流体动力学注射 hMET/突变型 β-连环蛋白之前调节饮食/AGE 含量：1) 高 AGE 背景诱发更早且更具侵袭性的 HCC，2) AGE 积累相关矩阵动力学发生显着变化——能量耗散或损失增加，在 AGE 和 AGE 受体中，响应变形而产生更快的应力松弛 (RAGE) 依赖性方式，3) 抑制 AGE 产生可逆转基质的变化我们将测试非体内粘弹性和降低肿瘤负荷的假设。肝硬化 T2DM/NASH AGEs 积聚导致基质粘弹性增加目标 1：我们建议研究饮食/AGE 含量、基质粘弹性、性别和 HCC 表型之间的联系我们将特别关注 AGE 如何介导。特定氨基酸上的胶原蛋白交联可以改变分子间识别和相互作用目标 2：我们将分析蛋白多糖对基质动力学的影响。 RAGE 和 AGER1 信号以及 AGE 累积对基质粘弹性参数和 HCC 的影响在目标 3 中，我们建议开发一种具有可调粘弹性的 3D 水凝胶系统。并基于RNAseq研究AGEs修饰的基质对细胞行为的影响。数据我们将重点关注细胞如何感知粘弹性变化的病理机制，以及赋予侵袭和迁移特性的关键基质细胞信号。这些研究将证明 AGE 对非肝硬化 NASH 中肝脏基质的影响并概述了促侵袭环境的病理机制。驱动入侵的信号将使我们能够在未来进行转化研究。