Hepatocyte Hippo Signaling Drives Inflammation in Liver Injury and Regeneration

肝细胞 Hippo 信号传导驱动肝脏损伤和再生中的炎症

• 批准号: 10259890
• 负责人: DEAN YIMLAMAI
• 金额: $ 12.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259890
• 关键词: Ablation; Address; Anti-Inflammatory Agents; Automobile Driving; Biology; Cell Communication; Cell Proliferation; Cells; Characteristics; Chronic; Cirrhosis; Conflict (Psychology); Cytometry; Data; Development; Disease; Environment; Extracellular Matrix; Fibrosis; Genetic; Genetic Transcription; Goals; Growth; Health; Hepatocyte; Hepatomegaly; High-Throughput RNA Sequencing; Homeostasis; ITGAM gene; Immune; Infiltration; Inflammation; Inflammatory; Injury; Knock-out; Lead; Literature; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Mediating; Medical; Modeling; Mus; Natural regeneration; Nature; Nonpenetrating Wounds; Organ; Outcome; PTPRC gene; Pathway interactions; Phenotype; Play; Population; Process; Publishing; Reagent; Recruitment Activity; Regenerative response; Regulatory Pathway; Reporting; Role; Signal Pathway; Signal Transduction; Source; Supporting Cell; Tissues; Work; arm; chemical genetics; chemokine; chronic liver injury; cytokine; experimental study; gain of function; genetic approach; improved; in vivo; inflammatory marker; lens; liver development; liver inflammation; liver injury; macrophage; monocyte; nonalcoholic steatohepatitis; overexpression; predictive modeling; programs; recruit; response; response to injury; therapeutic target; tissue regeneration; tool

Project Summary The short-term goal of this proposal is to define how hepatocyte Yap signaling influences the recruitment and characteristics of immune cell infiltration during liver injury and regeneration. Our long-term goal is to understand the intimate cell-cell interactions that hepatocytes have with the tissue microenvironment to drive liver fibrosis. Successful completion of this project would augment our ability to develop tailored medical therapies for cirrhosis by focusing on particular arms of the Hippo Signaling pathway. For several years, we studied the role that hepatocytes play in orchestrating regenerative responses, primarily through the lens of Hippo Signaling, a potent growth regulatory pathway. In a prior proposal (K08DK105351), we identified that by inducibly targeting hepatocytic Yap expression, this rapidly led to liver inflammation and fibrosis. We predicted that in a similar fashion, chronic liver injury would increase hepatocytic Yap activity and that this would directly lead to the development of liver inflammation/fibrosis. We have subsequently confirmed the predictions of that study. In the process, we identified that inflammation is directly related to Yap levels in hepatocytes and that Cyr61 is a key transcriptional target of Yap that is directly responsible for macrophage cell recruitment and liver fibrosis. This proposal seeks to extend these findings by using new tools to interrogate liver biology. In Aim 1, we will characterize the origin, phenotype and contribution of the monocytes/macrophages that respond to hepatocyte-specific Yap (Yap-Tg) activity in driving fibrosis. Using a combination of chemical and genetic strategies to modify monocytes/macrophages activity we will define their contribution to inflammation/fibrosis in the context of Yap-Tg. In Aim 2, we will interrogate the role of hepatocyte-derived Cyr61 in recruiting and polarizing monocytes through in vivo overexpression and genetic knockout experiments. Mass cytometry and high throughput RNA sequencing will be used to probe the immune landscape and changes in cellular signaling in the context of Cyr61 loss and gain of function. We propose that hepatocytes actively drive genetic programs after injury that remodel their local microenvironment. Hepatocytic Yap activity plays a critical role in directing these programs with Cyr61 being a particularly important downstream cytokine. Understanding the canonical and non-canonical mechanisms by which Yap/Cyr61 recruit and polarize the immune cell environment will lead to improved models of predicting the liver’s response to disease and facilitate directed treatment for cirrhosis.

项目摘要 该提案的短期目标是确定肝细胞雅普信号传导如何影响细胞的募集， 肝损伤和再生过程中免疫细胞浸润的特点。我们的长期目标是 了解肝细胞与组织微环境的密切细胞间相互作用， 肝纤维化该项目的成功完成将增强我们开发定制医疗产品的能力。 通过专注于Hippo Signaling通路的特定分支来治疗肝硬化。 几年来，我们研究了肝细胞在协调再生反应中的作用，主要是 通过河马信号的透镜，一种有效的生长调节途径。在先前的提案（K 08 DK 105351）中， 我们发现，通过诱导靶向肝细胞雅普表达，这迅速导致肝脏炎症， 纤维化我们预测，以类似的方式，慢性肝损伤将增加肝细胞雅普活性， 这将直接导致肝脏炎症/纤维化的发展。我们随后证实 这项研究的预测。在这个过程中，我们发现炎症与雅普水平直接相关， Cyr 61是雅普关键转录靶，直接负责巨噬细胞 细胞募集和肝纤维化。 该提案旨在通过使用新工具来询问肝脏生物学来扩展这些发现。在目标1中，我们 表征响应于以下的单核细胞/巨噬细胞的起源、表型和贡献： 肝细胞特异性雅普（Yap-Tg）活性在驱动纤维化中的作用。利用化学和基因的结合 我们将定义单核细胞/巨噬细胞对炎症/纤维化的贡献， Yap-Tg的背景。在目的2中，我们将探讨肝细胞衍生的Cyr 61在招募和调节细胞凋亡中的作用。 通过体内过表达和基因敲除实验极化单核细胞。质谱细胞仪和 高通量RNA测序将被用于探测免疫景观和细胞内的变化， 在Cyr 61功能丧失和获得的背景下的信号传导。 我们认为，肝细胞在损伤后积极驱动遗传程序，重塑其局部 微环境肝细胞雅普活性在指导这些程序中起着关键作用，Cyr 61是一种 尤其重要的下游细胞因子。理解规范和非规范机制， 其中雅普/Cyr 61招募和激活免疫细胞环境将导致改善的 预测肝脏对疾病的反应，促进肝硬化的定向治疗。