NASH-associated macrophages: regulation and role in disease pathogenesis

NASH 相关巨噬细胞：疾病发病机制中的调节和作用

• 批准号: 10675885
• 负责人: Jiandie D Lin
• 金额: $ 54.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675885
• 关键词: Ablation; Address; Adopted; Benign; Biology; Bone Marrow; Calcium; Cell Separation; Cells; Cirrhosis; Clinical; Data; Development; Development Plans; Diet; Dimensions; Disease; Disease Progression; Disease model; Exhibits; Fatty Liver; Fibrosis; Foundations; Future; Genetic; Genetic Models; Genetic Transcription; Hepatocyte; Heterogeneity; Homeostasis; Host Defense; Human; Inflammasome; Inflammation; Injury; Insulin Resistance; Knock-in; Knockout Mice; Knowledge; Link; Lipids; Liver; Liver Fibrosis; Macrophage; Malignant neoplasm of liver; Mediating; Membrane; Metabolic Diseases; Modeling; Molecular; Mus; Myelogenous; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity Epidemic; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pattern; Play; Population; Prevalence; Primary carcinoma of the liver cells; Public Health; Regulation; Risk; Role; Shapes; Signal Pathway; Signal Transduction; Stimulus; TGFBR1 gene; TREM2 gene; Therapeutic; Tissues; Transgenic Organisms; Urokinase; cell type; chronic liver injury; conditional knockout; design; dietary; effective therapy; end stage liver disease; genetic signature; genomic tools; insight; intrahepatic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; response; single-cell RNA sequencing; tool; transcriptome; transcriptomics; translational study; tumor microenvironment

Project Summary/Abstract The obesity epidemic has increased the prevalence of non-alcoholic fatty liver disease, which ranges from clinically benign hepatic steatosis to non-alcoholic steatohepatitis (NASH). The latter represents a more severe disease state featured by the presence of chronic liver injury, inflammation, and liver fibrosis, which increases the risk for end-stage liver disease such as cirrhosis and hepatocellular carcinoma (HCC). Macrophages play an integral role in host defense, tissue homeostasis, and disease progression. Altered macrophage polarization, characterized by changes in its transcriptional and functional states, has been causally linked to the pathogenesis of metabolic disease including NASH. Despite this, the nature of macrophage heterogeneity, disease-associated reprogramming, and its contribution to NASH progression remains obscure. To address these challenges, we recently performed single-cell RNA sequencing analysis on liver cells isolated from healthy and diet-induced NASH mice. Our study uncovered a unique population of NASH-associated macrophages (NAMs) that exhibits strong association with mouse and human NASH. Several important questions emerge from these findings regarding the pathophysiological signals that trigger NAM induction, its role in NASH pathogenesis, and the underlying mechanisms. Based on a body of preliminary data, we hypothesize that intrahepatic pathogenic stimuli drive NAM induction during NASH, thereby reshaping the liver microenvironment and exacerbating disease progression. In this proposal, we plan to elucidate the signaling pathways that promote NAM induction and critically assess its role in disease pathogenesis. We plan to explore the mechanisms through which NAMs contribute to the reprogramming of the liver microenvironment.

项目概要/摘要 肥胖流行增加了非酒精性脂肪肝的患病率，其范围包括 临床良性肝脂肪变性至非酒精性脂肪性肝炎（NASH）。后者代表着更严重的 以慢性肝损伤、炎症和肝纤维化为特征的疾病状态，这会增加 终末期肝病如肝硬化和肝细胞癌（HCC）的风险。巨噬细胞发挥作用 在宿主防御、组织稳态和疾病进展中发挥着不可或缺的作用。改变的巨噬细胞 极化，其特征是转录和功能状态的变化，与 包括 NASH 在内的代谢性疾病的发病机制。尽管如此，巨噬细胞异质性的本质， 疾病相关的重编程及其对 NASH 进展的贡献仍然不清楚。致地址 针对这些挑战，我们最近对从肝细胞中分离出的肝细胞进行了单细胞 RNA 测序分析 健康和饮食诱导的 NASH 小鼠。我们的研究发现了一个与 NASH 相关的独特人群 巨噬细胞 (NAM) 与小鼠和人类 NASH 密切相关。几个重要的 这些发现引发了关于触发 NAM 诱导的病理生理信号、其 NASH 发病机制中的作用及其潜在机制。根据大量初步数据，我们 假设 NASH 期间肝内致病刺激驱动 NAM 诱导，从而重塑肝脏 微环境并加剧疾病进展。在本提案中，我们计划阐明信号传导 促进 NAM 诱导并严格评估其在疾病发病机制中的作用的途径。我们计划 探索 NAM 促进肝脏微环境重新编程的机制。