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

基本信息

批准号：
10276602
负责人：
DEAN YIMLAMAI
金额：
$ 43.52万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10276602
关键词：
Acute Address Affect Behavior Biochemical Biochemical Pathway Biochemistry Cell Communication Cell Proliferation Cells Characteristics Chronic Cirrhosis Complex Data Development Endothelial Cells Enterobacteria phage P1 Cre recombinase Environment Epithelial Epithelial Cells 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 Lead Liver Liver Cirrhosis Liver Fibrosis Liver Regeneration Liver parenchyma Mediating Medical Modeling Myofibroblast Natural regeneration Nonpenetrating Wounds Organ Outcome Outcome Study Pathway interactions Phenotype Play Publishing Regenerative response Reporting Research Personnel Role Signal Pathway Signal Transduction Structure Therapeutic Work arm chemical genetics chemokine chromatin immunoprecipitation chronic liver injury differential expression extracellular genetic approach high dimensionality imaging approach improved liver inflammation liver injury macrophage monocyte next generation sequencing nonalcoholic steatohepatitis novel overexpression paralogous gene programs receptor recruit response response to injury tissue regeneration

Acute Address Affect Behavior Biochemical Biochemical Pathway Biochemistry Cell Communication Cell Proliferation Cells Characteristics Chronic Cirrhosis Complex Data Development Endothelial Cells Enterobacteria phage P1 Cre recombinase Environment Epithelial Epithelial Cells 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 Lead Liver Liver Cirrhosis Liver Fibrosis Liver Regeneration Liver parenchyma Mediating Medical Modeling Myofibroblast Natural regeneration Nonpenetrating Wounds Organ Outcome Outcome Study Pathway interactions Phenotype Play Publishing Regenerative response Reporting Research Personnel Role Signal Pathway Signal Transduction Structure Therapeutic Work arm chemical genetics chemokine chromatin immunoprecipitation chronic liver injury differential expression extracellular genetic approach high dimensionality imaging approach improved liver inflammation liver injury macrophage monocyte next generation sequencing nonalcoholic steatohepatitis novel overexpression paralogous gene programs receptor recruit response response to injury tissue regeneration

展开

项目摘要

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

项目摘要该提案的短期目标是了解YAP/TAZ/CYR61信号如何影响重塑的重塑急性和慢性损伤期间的肝实质。该建议将在功能上定义非副作用细胞（NPC）对上皮YAP/TAZ/CYR61信号的变化并验证候选者导致NPC激活和募集的信号通路。我们的长期目标是了解肝细胞对产生良好补偿器官做出的亲密相互作用和细胞决策。成功完成该项目将增强我们为肝硬化调整医疗疗法及其的能力续集通过重点关注YAP/TAZ/CYR61信号的特定臂。几年来，我们研究了YAP在策划再生反应中所起的作用。而yap（以及它的旁系同源物taz）在调节细胞增殖方面具有长期的作用，它们越来越多地成为被认为在适当的组织再生中具有重要的非细胞自主作用。 Yap和Taz共享类似的生化结构，但在受伤后差异表达。我们的工作以及其他人都建议 YAP和TAZ在肝损伤中被差异激活，并且可能具有常见和不同的生化靶向介导他们的伤害反应。我们建议密切检查我们的YAP和TAZ活动模型导致纤维化剖析每个分子的常见和不同机制。我们将进一步完善我们的了解CYR61是一个广泛报道的YAP/TAZ靶标的CYR61，据报道具有支持和抗纤维化角色。在AIM 1中，我们将与hepatocyte特异性激活YAP（YAP-TG）一起询问细胞细胞相互作用免疫细胞，肝正弦内皮细胞和成纤维细胞使用下一代测序和高级成像方法。化学和遗传方法询问了潜在驱动因素表型将在YAP-TG模型中使用，以检查其对肝星状细胞激活的影响。在AIM 2中，我们开发了一种具有与YAP-TG的独特特征的肝细胞特异性TAZ过表达模型。该TAZ模型显示出较少的炎症，但与YAP-TG模型相似的纤维化程度驱动独特的生化机制。我们将表征该模型的TAZ纤维化微环境并执行YAP-TG与TAZ过表达的深入基因组和转录分析。目标3意志研究CYR61可以作为促纤维化和抗纤维化分子的潜在机制，取决于在伤害设置上。我们建议对肝损伤，细胞和生化靶标将告知该领域有关关键检查点以限制或逆转肝硬化的发展。 PHS 398/2590（修订版06/09）页面延续格式页面