Dissecting the NRG4 hormonal checkpoint in metabolic liver disease

剖析代谢性肝病中的 NRG4 激素检查点

基本信息

批准号：
10447722
负责人：
Jiandie D Lin
金额：
$ 47.81万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447722
关键词：
Adipose tissue Attenuated Biological Biology CD8-Positive T-Lymphocytes Cells Chimeric Proteins Clinical Data Development Diet Disease Disease Progression Disease model Endocrine Exhibits Fatty acid glycerol esters Funding Genetic Models Half-Life Health Hepatic Hepatocarcinogenesis Hepatocyte Heterogeneity Homeostasis Hormonal Hormones Human Immune Immune checkpoint inhibitor Impairment Insulin Resistance Link Liver Liver diseases Malignant neoplasm of liver Mediating Metabolic Molecular Profiling Mus Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Pathogenesis Physiology Plasma Play Population Primary carcinoma of the liver cells Property Public Health Recombinant Proteins Recombinants Regulation Research Resolution Role Shapes Signal Transduction Stress T-Lymphocyte TREM2 gene Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Treatment Efficacy Tumor Immunity base cancer immunotherapy cell type cellular targeting design effective therapy exhaustion genomic tools good diet hormonal signals improved insight lipid biosynthesis liver injury liver metabolism loss of function macrophage mouse model neuregulin-4 non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel overexpression preservation single cell analysis single-cell RNA sequencing therapeutic development therapeutic target transcriptome transcriptome sequencing transcriptomics translational study

项目摘要

Inter-organ crosstalk via endocrine hormones is a fundamental feature of mammalian metabolic physiology. Disruptions of hormonal signaling have been linked to the development of insulin resistance, type 2 diabetes, and non-alcoholic steatohepatitis (NASH). We recently discovered Neuregulin 4 (NRG4) as a fat-derived hormone that is reduced in mouse and human obesity. Using gain- and loss-of-function mouse models, we demonstrated that NRG4 preserves metabolic health by acting on the liver to attenuate hepatic lipogenesis and stress-induced liver injury. These findings illustrate a novel adipose-hepatic hormonal axis mediated by NRG4 in metabolic signaling and disease pathogenesis. The non-parenchymal cells (NPCs) of the liver represent approximately 30% of total liver cells and play an important role in tissue homeostasis, hepatic metabolism, and disease progression. To delineate the landscape and regulation of liver cell heterogeneity, we performed single-cell RNA sequencing on NPCs isolated from healthy and diet-induced NASH mouse livers. This single-cell analysis revealed unprecedented insights into transcriptomic reprogramming of liver cells during NASH pathogenesis. Based on a body of preliminary data, we hypothesize that NRG4 signaling shapes the liver microenvironment to impinge on the progression of NASH and its associated liver disease. In this proposal, we plan to delineate how NRG4 regulates the transcriptomic and functional properties of liver cells at single-cell resolution. We will determine the mechanisms and significance of the regulation of hepatic immune cell landscape by NRG4 in mediating its effects on NASH pathogenesis. Finally, we plan to assess the therapeutic potential of targeting NRG4 for the treatment of metabolic liver disease.

通过内分泌激素间串扰串扰是哺乳动物代谢生理学的一个基本特征。激素信号的破坏与胰岛素抵抗，2型糖尿病和非酒精性脂肪性肝炎（NASH）的发展有关。我们最近发现神经蛋白4（NRG4）是一种减少小鼠和人肥胖症的脂肪激素。使用功能丧失的小鼠模型，我们证明了NRG4通过在肝脏上作用以减轻肝脂肪生成和应激诱导的肝损伤来保持代谢健康。这些发现说明了由NRG4在代谢信号传导和疾病发病机理中介导的新型脂肪 - 肝激素轴。肝脏的非核细胞（NPC）约占总肝细胞的30％，在组织稳态，肝代谢和疾病进展中起重要作用。为了描绘肝细胞异质性的景观和调节，我们对从健康和饮食诱导的纳什小鼠肝脏分离的NPC进行了单细胞RNA测序。该单细胞分析表明，在NASH发病机理期间，对肝细胞转录组重编程的前所未有的见解。基于初步数据的体系，我们假设NRG4信号传导塑造了肝微环境会影响NASH及其相关肝病的进展。在此提案中，我们计划要描述NRG4如何调节单细胞分辨率的肝细胞的转录组和功能特性。我们将通过NRG4来确定肝免疫细胞景观调节的机制和意义，从而介导其对NASH发病机理的影响。最后，我们计划评估靶向NRG4治疗代谢肝病的治疗潜力。