Deciphering Epithelial Signals in the Liver to Drive Inflammation and Fibrosis

破译肝脏中驱动炎症和纤维化的上皮信号

• 批准号: 10662454
• 负责人: DEAN YIMLAMAI
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662454
• 关键词: Acute; Address; Affect; Behavior; Biochemical; Biochemical Pathway; Biochemistry; Cell Communication; Cell Proliferation; Cells; Characteristics; Chemicals; Chronic; Cirrhosis; Compensation; Complex; Data; Decision Making; Development; Disparity; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Environment; Epithelial Cells; Epithelium; Fibroblasts; Fibrosis; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Goals; Health; Hepatic Stellate Cell; Hepatocyte; Immune; Inflammation; Inflammatory; Inflammatory Response; Injury; Liver; Liver Cirrhosis; Liver Fibrosis; Liver Regeneration; Liver parenchyma; Macrophage; Mediating; Medical; Modeling; Myofibroblast; Natural regeneration; Nonpenetrating Wounds; Organ; Outcome; Pathway interactions; Phenotype; Play; Publishing; Regenerative response; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Structure; Therapeutic; Work; arm; candidate validation; chemokine; chromatin immunoprecipitation; chronic liver injury; differential expression; extracellular; genetic approach; high dimensionality; imaging approach; improved; liver inflammation; liver injury; monocyte; next generation sequencing; nonalcoholic steatohepatitis; novel; overexpression; paralogous gene; programs; receptor; recruit; response; response to injury; tissue regeneration

Project Summary The short-term goal of this proposal is to understand how Yap/Taz/Cyr61 signaling influences remodeling of the liver parenchyma during acute and chronic injury. This proposal will functionally define the response of non-parenchymal cells (NPCs) to changes in epithelial Yap/Taz/Cyr61 signaling and validate candidate signaling pathways that lead to NPC activation and recruitment. Our long-term goal is to understand the intimate interactions and cellular decisions made by liver cells to generate a well-compensated organ. Successful completion of this project would augment our ability to tailor medical therapies for cirrhosis and its sequela by focusing on particular arms of Yap/Taz/Cyr61 signaling. For several years, we studied the role that Yap plays in orchestrating regenerative responses. While Yap (and, its paralog Taz) have long-established roles in regulating cell proliferation, they are increasingly being recognized as having important non-cell-autonomous roles in proper tissue regeneration. Yap and Taz share a similar biochemical structure but are differentially expressed after injury. Our work as well as of others suggest that Yap and Taz are differentially activated in liver injury and, likely have common and distinct biochemical targets mediating their injury response. We propose to closely examine our models of Yap and Taz activity that lead to fibrosis to dissect common and distinct mechanisms for each molecule. We will further refine our understanding of Cyr61, a widely reported Yap/Taz target which has been reported to have both pro- and anti- fibrotic roles. In Aim 1, we will interrogate the cell-cell interactions after hepatocyte-specific activation of Yap (Yap-Tg) with immune cells, liver sinusoidal endothelial cells, and fibroblasts using next-generation sequencing and advanced imaging approaches. Chemical and genetic approaches interrogating potential drivers of the phenotype will be used in the Yap-Tg model to examine its effects on hepatic stellate cell activation. In Aim 2, we developed a hepatocyte-specific Taz overexpression model with distinctive characteristics from Yap-Tg. This Taz model displays less inflammation, but a similar degree of fibrosis as the Yap-Tg model suggesting it drives unique biochemical mechanisms. We will characterize the Taz fibrotic microenvironment of this model and perform in-depth genomic and transcriptional profiling of Yap-Tg versus Taz overexpression. Aim 3 will investigate potential mechanisms that Cyr61 can operate as a pro-fibrotic and anti-fibrotic molecule depending on the injury setting. We propose that a detailed understanding of epithelial Yap/Taz/Cyr61 signaling in liver injury, their cellular and biochemical targets will inform the field regarding critical checkpoints to limit or reverse cirrhotic development. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

项目摘要 本研究的短期目标是了解雅普/Taz/Cyr 61信号通路如何影响细胞的重塑。 急性和慢性损伤期间的肝实质。本提案将从功能上界定 非实质细胞（NPC）对上皮雅普/Taz/Cyr 61信号传导变化的影响并验证候选细胞 导致NPC激活和募集的信号通路。我们的长期目标是了解 肝细胞通过密切的相互作用和细胞决定来产生一个补偿良好的器官。 该项目的成功完成将增强我们为肝硬化及其 通过关注雅普/Taz/Cyr 61信号传导的特定臂， 几年来，我们研究了雅普在协调再生反应中所起的作用。而雅普（和， 它的副产物Taz）在调节细胞增殖方面具有长期确立的作用，它们越来越多地被 被认为在适当的组织再生中具有重要的非细胞自主作用。雅普和塔兹 相似的生化结构，但在损伤后差异表达。我们和其他人的研究表明 雅普和Taz在肝损伤中被不同地激活，并且可能具有共同的和不同的生化特性。 介导其损伤反应的靶点。我们建议仔细检查我们的雅普和塔兹活动模型， 导致纤维化来剖析每个分子的共同和不同机制。我们将进一步完善我们的 Cyr 61是一种被广泛报道的雅普/Taz靶点，据报道它具有亲和抗- 纤维化的作用。 在目的1中，我们将询问肝细胞特异性激活雅普（Yap-Tg）后的细胞-细胞相互作用， 免疫细胞、肝窦内皮细胞和成纤维细胞， 先进的成像方法。化学和遗传学方法询问潜在的驱动因素， 表型将用于Yap-Tg模型，以检查其对肝星状细胞活化的影响。在目标2中， 我们开发了一种肝细胞特异性Taz过表达模型，该模型具有与Yap-Tg不同的特征。 这种Taz模型显示较少的炎症，但与Yap-Tg模型相似的纤维化程度表明， 驱动着独特的生化机制我们将描述该模型的Taz纤维化微环境 并对Yap-Tg与Taz过表达进行深入的基因组和转录分析。目标3将 研究Cyr 61可以作为促纤维化和抗纤维化分子作用的潜在机制， 在受伤的情况下 我们建议详细了解上皮细胞雅普/Taz/Cyr 61信号在肝损伤中的作用， 生物化学靶标将告知现场关于限制或逆转肿瘤发展的关键检查点。 PHS 398/2590（Rev.06/09）