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

项目总结