Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression

肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制

基本信息

项目摘要

Non-alcoholic fatty liver disease (NAFLD) develops as a result of fat deposited into the liver (steatosis) caused by other factors aside from alcohol; and, NAFLD is now the most common liver disease in Western developed countries. If left untreated or if another insult occurs (“two-hit” hypothesis), NAFLD can develop into NASH. While hepatocytes are believed to be the primary cell involved in NAFLD, new studies have demonstrated that both cholangiocytes and mast cells (MCs) contribute to NAFLD progression and potentially to NAFLDèNASH transition. Further, damaged cholangiocytes undergo senescence and take on a senescence-associated secretory phenotype (SASP), which may also contribute to the inflammatory environment seen in NASH. MCs are found in adipose tissue of obese patients and histamine levels are increased in patients with NAFLD, NASH and end-stage liver disease. To date, no successful treatments have been developed for NAFLD, aside from altering diet and lifestyle; and, there have been no studies to examine the potential paracrine interaction between cholangiocytes and MCs in models of NAFLD. Further, the synergistic relationship between MCs, cholangiocytes, hepatic stellate cells (HSCs) and Kupffer cells has not been fully examined. The premise of the study is supported by: (i) previous work demonstrating that both cholangiocytes and MCs contribute to NAFLD; (ii) work from the PI demonstrating that MCs contribute to liver damage and are critical regulators of disease progression; and, (iii) preliminary data showing that there is a direct interaction between cholangiocytes and MCs that influences hepatic damage, Kupffer cell activation/inflammation and HSC-driven fibrosis during NAFLD. In SA1, the PI will examine biliary-induced MC migration using mice subjected to HFD/HFCS and Vivo-Morpholino treatments to inhibit biliary senescence. This aim will focus primarily on the interactions between cholangiocytes and MCs. SA2 will focus on the contribution of MCs to NAFLD progression by using a genetic model of MC depletion and also reintroduction of MCs. These studies allow us to examine the effects of losing MCs, but also to determine if MCs perpetuate NAFLD progression and potentially NAFLD to NASH transition (marked by enhanced liver inflammation). Finally, in SA3, the PI will focus on the inhibition of MC-derived histamine and TGF-b1 using pharmaceutical inhibition to directly target this inflammatory molecule. Preliminary data and previous publications reveal that TGF-b1 may be a key modulator of NAFLD and liver damage (including fibrosis); and, MC-derived histamine regulates TGF-b1 expression and secretion. In all of proposed aims, the PI will evaluate NAFLD induced by both Western Diet (HFD/HFCS) and the methionine-choline deficient (MCD) diet. In addition, features of metabolic syndrome including insulin resistance, elevated triglycerides, lipoprotein abnormalities, and glucose intolerance will be evaluated. Targeting MC mediators may be a beneficial therapeutic approach to managing NAFLD progression.!
非酒精性脂肪肝 (NAFLD) 是由于脂肪沉积到肝脏(脂肪变性)引起的 除酒精以外的其他因素;而且,NAFLD现在是西方发达国家最常见的肝脏疾病 国家。如果不及时治疗或发生另一次损伤(“两次打击”假设),NAFLD 可能会发展为 NASH。 虽然肝细胞被认为是参与 NAFLD 的主要细胞,但新的研究表明, 胆管细胞和肥大细胞 (MC) 均会导致 NAFLD 进展,并可能导致 NAFLDèNASH 过渡。此外,受损的胆管细胞会经历衰老​​并呈现出与衰老相关的特征。 分泌表型(SASP),这也可能导致 NASH 中的炎症环境。 MC 存在于肥胖患者的脂肪组织中,并且 NAFLD 患者的组胺水平升高, NASH 和终末期肝病。迄今为止,尚未开发出成功的 NAFLD 治疗方法, 除了改变饮食和生活方式;并且,还没有研究来检验潜在的 NAFLD 模型中胆管细胞和 MC 之间的旁分泌相互作用。此外,协同 MC、胆管细胞、肝星状细胞(HSC)和库普弗细胞之间的关系尚未完全阐明 检查了。该研究的前提得到以下支持:(i)先前的工作表明,胆管细胞 MC 会导致 NAFLD; (ii) PI 的工作证明 MC 会导致肝损伤,并且 疾病进展的关键调节因子; (iii) 初步数据表明存在直接相互作用 胆管细胞和 MC 之间的相互作用,影响肝损伤、库普弗细胞活化/炎症和 NAFLD 期间 HSC 驱动的纤维化。在 SA1 中,PI 将使用小鼠检查胆道诱导的 MC 迁移 接受 HFD/HFCS 和 Vivo-Morpholino 治疗以抑制胆道衰老。这一目标将集中 主要是胆管细胞和MC之间的相互作用。 SA2 将重点关注 MC 的贡献 通过使用 MC 耗竭和重新引入 MC 的遗传模型来进展 NAFLD。这些研究 让我们能够检查失去 MC 的影响,同时还可以确定 MC 是否会延续 NAFLD 的进展以及 潜在的 NAFLD 向 NASH 转变(以肝脏炎症增强为标志)。最后,在 SA3 中,PI 将 重点关注利用药物抑制直接靶向抑制 MC 衍生的组胺和 TGF-b1 这种炎症分子。初步数据和之前的出版物表明 TGF-b1 可能是关键 NAFLD 和肝损伤(包括纤维化)的调节剂;并且,MC 衍生的组胺调节 TGF-b1 表达和分泌。在所有提出的目标中,PI 将评估西方饮食引起的 NAFLD (HFD/HFCS)和蛋氨酸胆碱缺乏(MCD)饮食。此外,代谢综合征的特点 包括胰岛素抵抗、甘油三酯升高、脂蛋白异常和葡萄糖不耐症 评价。针对 MC 介质可能是管理 NAFLD 的有益治疗方法 进展.!

项目成果

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Heather L Francis其他文献

Heather L Francis的其他文献

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{{ truncateString('Heather L Francis', 18)}}的其他基金

Mast Cell Regulation of Alcohol-Induced Liver Damage
肥大细胞对酒精引起的肝损伤的调节
  • 批准号:
    10539568
  • 财政年份:
    2022
  • 资助金额:
    $ 35.23万
  • 项目类别:
Mast Cell Regulation of Alcohol-Induced Liver Damage
肥大细胞对酒精引起的肝损伤的调节
  • 批准号:
    10686244
  • 财政年份:
    2022
  • 资助金额:
    $ 35.23万
  • 项目类别:
BLR&D Research Career Scientist Award
BLR
  • 批准号:
    10618234
  • 财政年份:
    2020
  • 资助金额:
    $ 35.23万
  • 项目类别:
BLR&D Research Career Scientist Award
BLR
  • 批准号:
    10454100
  • 财政年份:
    2020
  • 资助金额:
    $ 35.23万
  • 项目类别:
Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
  • 批准号:
    9764884
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage
胆管/胆管细胞修复和损伤过程中肥大细胞的旁分泌调节
  • 批准号:
    9923327
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
  • 批准号:
    9982325
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression
肥大细胞/胆管细胞对非酒精性脂肪肝疾病进展的调节机制
  • 批准号:
    10170334
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage
胆管/胆管细胞修复和损伤过程中肥大细胞的旁分泌调节
  • 批准号:
    9980878
  • 财政年份:
    2019
  • 资助金额:
    $ 35.23万
  • 项目类别:
Mechanisms of synergistic regulation of biliary inflammation and fibrosis
胆道炎症和纤维化的协同调节机制
  • 批准号:
    9890864
  • 财政年份:
    2016
  • 资助金额:
    $ 35.23万
  • 项目类别:

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