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：
10597033
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/10597033
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 Hyperlipidemia 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 Nose Obesity Pathogenesis Pathogenicity Patients Phenotype Plasminogen Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor beta Receptor Population 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 permissiveness prevent promoter public health priorities receptor senescence single-cell RNA sequencing therapeutic target tool transcriptome transcriptomics transdifferentiation 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，肝细胞损伤，感染，纤维化和肝细胞癌（HCC）。一个未解决的关键问题是炎症和肝纤维化如何产生“促癌基质”，促进的发展肝细胞癌（HCC），即使没有共存的肝硬化也是如此。这些基础变化的核心是肝星状细胞（HSC）的激活，它们是居民collesinosoidal，富含维生素A的细胞，这些细胞富含维生素A 转差成肌纤维细胞（与癌症相关的成纤维细胞或CAF）分泌一大批细胞外基质构成，生长因子和细胞因子。这项研究的目的是阐明肝的作用 NASH和HCC发病机理中的星状细胞。我们和我们的合作者已经开发了两个高效，完善的HSC部署模型，可以解决关键的差距，以理解其在 NASH纤维化和HCC：1）Jedi（“仅EGFP死亡诱导”）T细胞，其中CD8+ T细胞设计用于杀死向转基因小鼠施用表达绿色荧光蛋白（GFP）的细胞，其中GFP是驱动的由B-PDGF受体启动子杀死99％的HSC； 2）靶向尿激酶纤溶酶原的CAR T细胞活化的受体（UPAR），仅消除鼠肝脏中的感觉HSC。同时，我们创建了高度可复制的鼠NASH模型，忠实地复制了组织学，纤维化进展和HCCS 人类纳什。我们的中心假设是Nash Express独特驱动程序中的激活和感觉HSC 这有助于易于肿瘤的基质微环境。这，该提案同时调查了 HSC对NASH的动态和独特的贡献，以及它们产生的基质异常到HCC。我们将以三个相互关联但独特的特定目的解决这一假设：1）定义 HSC在其部署在正常和NASH之前和之后的动力学，起源和细胞特征小鼠； 2）建立感官和非感知HSC对NASH纤维化和的相对贡献 HCC; 3）识别鼠和人纳什中HCC的HSC衍生的基质驱动器。这种创新的方法利用独特的动物模型很重要，因为它将产生基本的新见解，以对HSC生物学在健康和疾病中，定义了它们调节的特定基质驱动因素，并连接小鼠的异常人类NASH-HCC的模型以建立其临床相关性作为潜在的治疗靶点。