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: 10436378
• 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/10436378
• 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

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

项目概要 该提案的短期目标是了解 Yap/Taz/Cyr61 信号如何影响重塑 急性和慢性损伤期间的肝实质。该提案将在功能上定义响应 非实质细胞 (NPC) 改变上皮 Yap/Taz/Cyr61 信号传导并验证候选者 导致 NPC 激活和招募的信号通路。我们的长期目标是了解 肝细胞的密切相互作用和细胞决策产生了补偿良好的器官。 该项目的成功完成将增强我们为肝硬化及其相关疾病量身定制医疗疗法的能力 通过关注 Yap/Taz/Cyr61 信号传导的特定臂来产生后遗症。 多年来，我们研究了 Yap 在协调再生反应中所扮演的角色。虽然雅普（并且， 它的旁系同源物 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。 Yap 和 Taz 共享一个 相似的生化结构，但损伤后表达差异。我们的工作以及其他人的工作表明 Yap 和 Taz 在肝损伤中的激活程度不同，并且可能具有共同和不同的生化特征 调节他们的伤害反应的目标。我们建议仔细检查我们的 Yap 和 Taz 活动模型 导致纤维化来剖析每个分子的常见和独特机制。我们将进一步完善我们的 Cyr61 是一个被广泛报道的 Yap/Taz 靶点，据报道它具有支持和反对作用 纤维化的作用。 在目标 1 中，我们将探究 Yap (Yap-Tg) 肝细胞特异性激活后的细胞间相互作用 使用新一代测序技术对免疫细胞、肝窦内皮细胞和成纤维细胞进行研究 先进的成像方法。化学和遗传学方法探究潜在的驱动因素 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，具有与 Yap-Tg 不同的特征。 该 Taz 模型显示出较少的炎症，但纤维化程度与 Yap-Tg 模型相似 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 Cyr61 作为促纤维化和抗纤维化分子的潜在机制，具体取决于 关于伤害设定。 我们建议详细了解肝损伤中的上皮 Yap/Taz/Cyr61 信号传导、其细胞和 生化目标将为该领域提供有关限制或逆转肝硬化发展的关键检查点的信息。 PHS 398/2590（修订版 06/09） 页面延续 格式页面