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Deciphering Epithelial Signals in the Liver to Drive Inflammation and Fibrosis

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:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-07-01 至 2026-06-30

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中文摘要
翻译
项目摘要 该提案的短期目标是了解YAP/Taz/Cyr61信号如何影响血管重构 急性和慢性损伤时的肝实质。这项提案将在功能上定义 非实质细胞对上皮细胞YAP/Taz/Cyr61信号变化的影响及候选验证 导致NPC激活和招募的信号通路。我们的长期目标是了解 由肝细胞进行的亲密相互作用和细胞决策,以产生一个补偿良好的器官。 这个项目的成功完成将增强我们为肝硬变及其疾病量身定做药物治疗的能力。 后遗症通过集中在YAP/Taz/Cyr61信号的特定手臂上。 在几年的时间里,我们研究了YAP在组织再生反应中所扮演的角色。而YAP(和, 它的Paralog Taz)在调节细胞增殖方面有着长期确立的作用,它们正在越来越多地 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,但在损伤后表达差异。我们的工作以及其他人的工作都表明 YAP和TAZ在肝脏损伤中被不同地激活,可能具有共同和不同的生化 目标调解他们的伤害反应。我们建议仔细检查我们的YAP和TAZ活动模型 导致纤维化,以剖析每个分子的共同和不同的机制。我们将进一步完善我们的 对Cyr61的理解,广泛报道的YAP/Taz靶标,据报道既有支持也有反对 纤维化的作用。 在目标1中,我们将询问肝细胞特异性激活YAP(YAP-TG)后细胞与细胞的相互作用 免疫细胞、肝窦内皮细胞和成纤维细胞 先进的成像方法。化学和遗传方法审问潜在的驱动因素 表型将用于YAP-TG模型,以检测其对肝星状细胞激活的影响。在目标2中, 我们从YAP-TG中建立了一个具有明显特征的肝细胞特异性Taz过表达模型。 TAZ模型显示炎症较少,但纤维化程度与YAP-TG模型相似 驱动独特的生化机制。我们将对该模型的TAZ纤维化微环境进行表征 并对YAP-TG和Taz过表达进行深入的基因组和转录图谱分析。目标3将 探讨Cyr61作为促肝纤维化和抗肝纤维化分子的可能机制 在受伤的背景下。 我们认为,对肝损伤中上皮性YAP/Taz/Cyr61信号的详细理解,其细胞和 生化指标将告知现场有关关键检查点的信息,以限制或逆转肝硬变的发展。 PHS 398/2590(06/09版)页面续格式页面
英文摘要
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
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Deciphering Epithelial Signals in the Liver to Drive Inflammation and Fibrosis
  • 批准号:
    10276602
  • 项目类别:
  • 资助金额:
    $43.52万
  • 财政年份:
    2021
  • 负责人:
    DEAN YIMLAMAI
  • 依托单位:
Deciphering Epithelial Signals in the Liver to Drive Inflammation and Fibrosis
  • 批准号:
    10662454
  • 项目类别:
  • 资助金额:
    $41.88万
  • 财政年份:
    2021
  • 负责人:
    DEAN YIMLAMAI
  • 依托单位:
Hepatocyte Hippo Signaling Drives Inflammation in Liver Injury and Regeneration
  • 批准号:
    10259890
  • 项目类别:
  • 资助金额:
    $12.56万
  • 财政年份:
    2020
  • 负责人:
    DEAN YIMLAMAI
  • 依托单位:
Hippo Signaling Mediates the Development of Liver Fibrosis
海外基金