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Hepatic stellate cells in NASH fibrosis and HCC

NASH 纤维化和 HCC 中的肝星状细胞

基本信息

批准号：
10350710
负责人：
SCOTT L. FRIEDMAN
金额：
$ 49.47万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10350710
关键词：
Address Affect American Animal Model Animals Behavior CD8-Positive T-Lymphocytes Cells Cellular biology Cessation of life Chronic Cicatrix Cirrhosis Clinical Coupled Data Development Disease Extracellular Matrix Fibroblasts Fibrosis Goals Green Fluorescent Proteins Growth Factor Health Hepatic Stellate Cell Histologic Histology Homeostasis Human Hypertension Individual Inflammation Knowledge Ligation Link Liver Liver Fibrosis Liver diseases Malignant Neoplasms Malignant neoplasm of liver Metabolic syndrome Metagenomics Methods Mission Modeling Mus Myofibroblast National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathogenicity Patients Phenotype Plasminogen Platelet-Derived Growth Factor beta Receptor Positioning Attribute Prevalence Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Public Health Reproducibility Research Role Source Stromal Change System T-Cell Depletion T-Lymphocyte Testing Tissues Transgenic Mice Urokinase Viral hepatitis Vitamin A bile duct carcinogenicity cell killing chimeric antigen receptor T cells clinically relevant cytokine defined contribution engineered T cells gene regulatory network hepatocyte injury improved innovation insight liver injury morphometry mouse model new therapeutic target nonalcoholic steatohepatitis prevent promoter public health priorities receptor senescence single-cell RNA sequencing therapeutic target tool transcriptome transcriptomics tumor

项目摘要

Non-alcoholic steatohepatitis (NASH) is a rising public health threat characterized by progression from steatosis, to hepatocyte injury, inflammation, fibrosis and hepatocellular carcinoma (HCC). A key unanswered question is how inflammation and hepatic fibrosis create a ‘pro-carcinogenic stroma’ that promotes the development of hepatocellular carcinoma (HCC), even without co-existent cirrhosis. Central to these stromal changes is the activation of hepatic stellate cells (HSCs), which are resident perisinusoidal, vitamin A-rich cells that transdifferentiate into myofibroblasts (cancer-associated fibroblasts, or CAFs) to secrete a host of extracellular matrix constituents, growth factors, and cytokines. The objective of this research is to clarify the role of hepatic stellate cells in the pathogenesis of NASH and HCC. We and our collaborators have developed two highly efficient, complementary models of HSC depletion that can address critical gaps in understanding their role in NASH fibrosis and HCC: 1) JEDI (“Just EGFP death inducing”) T-cells, in which CD8+ T cells engineered to kill cells that express green fluorescent protein (GFP) are administered to transgenic mice, in which GFP is driven by the b-PDGF receptor promoter, killing 99% of HSCs; 2) CAR T cells targeting urokinase plasminogen activated receptor (uPAR), which eliminate only senescent HSCs in murine liver. Concurrently, we have created a highly reproducible murine NASH model that faithfully replicates the histology, fibrosis progression and HCCs of human NASH. Our central hypothesis is that activated and senescent HSCs in NASH express unique drivers that contribute to a tumor-prone stromal microenvironment. Thus, this proposal concurrently investigates the dynamics and unique contributions of HSCs to NASH, and the stromal abnormalities they generate that give rise to HCC. We will address this hypothesis in three interrelated, but distinct Specific Aims:1) To define the dynamics, origin and cellular features of HSC repopulation before and after their depletion in normal and NASH mice; 2) To establish the relative contributions of senescent and non-senescent HSCs to NASH fibrosis and HCC; 3) To identify HSC-derived stromal drivers of HCC in murine and human NASH. This innovative approach leveraging unique animal models is significant because it will yield fundamental new insights into HSC biology in health and disease, define specific stromal drivers that they regulate, and link abnormalities from mouse models to human NASH-HCC to establish their clinical relevance as potential therapeutic targets.

非酒精性脂肪性肝炎（NASH）是一种不断上升的公共卫生威胁，其特征是脂肪变性进展。