Hepatic TrkB-T1 signaling in NASH pathogenesis and resolution

NASH 发病机制和解决方案中的肝脏 TrkB-T1 信号传导

• 批准号: 10675970
• 负责人: Jiandie D Lin
• 金额: $ 57.87万
• 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/10675970
• 关键词: Ablation; Address; Automobile Driving; Binding; Biology; Brain-Derived Neurotrophic Factor; Cell Death; Cells; Chimeric Proteins; Data; Diet; Disease; Disease Progression; Disease model; Fatty Liver; Fibrosis; Functional disorder; Future; Genetic Models; Hepatic; Hepatocyte; Heterogeneity; Human; Inflammation; Injury; Knockout Mice; Knowledge; Length; Ligands; Link; Liver; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Modeling; Molecular; Mus; NF-kappa B; Nature; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phosphotransferases; Protein Isoforms; Proteins; Recombinants; Resolution; Role; Shapes; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Translational Research; Treatment Efficacy; Tropomyosin; Work; cell type; design; effective therapy; efficacy evaluation; fatty liver disease; feeding; genomic tools; hepatocyte injury; improved; insight; intrahepatic; liver injury; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; overexpression; pre-clinical; protective effect; receptor; therapeutic development; tool; transcriptome sequencing; transcriptomics

Project Summary/Abstract Nonalcoholic steatohepatitis (NASH) is a progressive metabolic liver disease characterized by persistent liver injury, inflammation, and fibrosis. Reprogramming of intrahepatic signaling and liver microenvironment is a hallmark of NASH pathogenesis in mice and humans. However, the molecular nature of pathophysiological signaling that drives NASH progression remains an important unsolved question. To address this critical knowledge gap, we performed bulk and single-cell transcriptomic analysis on healthy and diet-induced NASH mouse livers. Our work revealed several transcriptomic signatures of NASH, liver cell heterogeneity and reprogramming during disease pathogenesis, and the landscape of intercellular crosstalk in the liver. Importantly, key features of NASH-associated reprogramming of the liver microenvironment and intrahepatic signaling in mice are notably conserved in human NASH. Hepatocytes respond to metabolic stresses in NASH by engaging adaptive and maladaptive signaling pathways that ultimately lead to liver steatosis and hepatocyte injury. In preliminary studies, we observed that hepatic expression of the truncated isoform of Tropomyosin receptor kinase B (TrkB), TrkB-T1, but not the full-length TrkB isoform, was selectively and markedly upregulated in mouse and human NASH. However, whether and how aberrant activation of hepatic TrkB-T1 signaling contributes to NASH pathogenesis has not been explored. Based on a body of preliminary data, we hypothesize that pathogenic activation of TrkB-T1 signaling sensitizes hepatocytes to stress-induced injury. In this proposal, we plan to investigate the role of TrkB-T1 in liver injury and NASH progression. We will explore cell-intrinsic and extrinsic mechanisms that mediate the effects of TrkB-T1 on NASH pathogenesis. Finally, we will explore the therapeutic potential of targeting this pathway for NASH treatment. Successful completion of this project will provide novel insights into the pathophysiology of NASH and generate critical preclinical data that will guide future translational work.

项目总结/摘要 非酒精性脂肪性肝炎（NASH）是一种进行性代谢性肝病， 损伤、炎症和纤维化。肝内信号转导和肝脏微环境的重编程是一个重要的研究领域。 在小鼠和人类中NASH发病机制的标志。然而，病理生理学的分子本质 驱动NASH进展的信号传导仍然是一个重要的未解决的问题。处理这个关键 我们对健康和饮食诱导的NASH进行了大量和单细胞转录组学分析 小鼠肝脏。我们的工作揭示了NASH的几个转录组特征，肝细胞异质性和 疾病发病过程中的重编程，以及肝脏中细胞间串扰的景观。 重要的是，NASH相关的肝脏微环境和肝内微环境的重编程的关键特征， 小鼠中的信号传导在人NASH中显著保守。NASH中肝细胞对代谢应激的反应 通过参与适应性和适应不良的信号通路，最终导致肝脏脂肪变性和肝细胞 损伤在初步研究中，我们观察到肝表达的原肌球蛋白的截断亚型， 受体激酶B（Trk B），Trk B-T1，而不是全长Trk B亚型，被选择性地和显著地 在小鼠和人NASH中上调。然而，肝TrkB-T1是否以及如何异常激活， 信号传导对NASH发病机制的作用尚未研究。根据初步数据，我们 假设TrkB-T1信号传导致病性激活使肝细胞对应激诱导的损伤敏感。在 根据这一提议，我们计划研究TrkB-T1在肝损伤和NASH进展中的作用。我们将探讨 介导TrkB-T1对NASH发病机制的作用的细胞内在和外在机制。最后我们 将探索靶向这一途径治疗NASH的治疗潜力。成功完成 该项目将为NASH的病理生理学提供新的见解，并产生关键的临床前数据 这将指导未来的翻译工作。