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Role of necroptosis in inflammation and NAFLD to HCC progression

Role of necroptosis in inflammation and NAFLD to HCC progression
坏死性凋亡在炎症和 NAFLD 与 HCC 进展中的作用
批准号:
10429756
负责人:
Deepa Sathyaseelan
金额:
$7.25万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-03-01 至 2024-02-29

项目摘要

项目成果

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中文摘要
翻译
项目摘要/摘要 研究目的是确定肥胖介导的肝细胞慢性炎症的来源 癌症(HCC)。肝细胞癌是肝癌的一种主要形式,是导致 全球与癌症相关的死亡人数。近年来,肥胖已成为主要和独立的风险因素。 对于肝癌,预计到2030年,肝癌将成为美国癌症相关死亡的第三大原因 由于肥胖症的流行。肥胖导致的非酒精性脂肪性肝病(NAFLD),影响近25%的 美国人口,是肥胖人群中肝细胞癌的关键驱动因素。尽管肥胖症之间有很强的联系 和肝细胞癌,在肥胖中驱动肝细胞癌发展的机制还不清楚。非解析 慢性炎症是肥胖和损害中肝细胞癌发生和发展的主要因素 相关分子模式(DAMP)是目前认为的肝细胞癌的介体之一。坏死性下垂是一种 程序性细胞死亡已被证明通过释放湿气在炎症中发挥主要作用, 它们与免疫细胞的细胞表面受体结合,从而诱导炎症。在本申请中,我们建议 NAFLD中的肝细胞坏死性下垂是肝细胞癌进展的关键因素。我们的初步数据支持 肝细胞癌中的坏死性下垂,例如,使用RIPK3-/-或MLKL-/-小鼠阻断坏死性下垂可减少肝脏炎症, 胆碱缺乏-高脂饮食(CD-HFD)喂养的小鼠天然免疫细胞的渗透和肝癌的发病率 不要导致肥胖。在自发性肝癌遗传小鼠模型(SOD1-/-小鼠)中,使用 坏死性下垂抑制物Necrostatin-1s可减少肝脏坏死性下垂、炎症和肝细胞癌的途径 发展。基于此,我们认为肝细胞坏死性下垂是肝脏炎症的主要来源。 在启动肝细胞癌的微环境中。我们假设非酒精性脂肪肝进展为肝细胞癌是由于 肝细胞坏死性下垂引起的炎症增加和预防坏死性下垂将 减少炎症和非酒精性脂肪肝进展为肝细胞癌。这一假设将通过基因测试进行验证 靶向RIPK3或MLKL的途径阻断或激活肝细胞中的坏死性下垂 坏死下垂途径,并评价其对炎症和肝细胞癌的作用。在目标1中,坏死性下垂将专门 利用肝细胞特异性RIPK3或MLKL基因敲除小鼠在肝细胞中减少/阻断,并确定是否阻断 肝细胞坏死性下垂可减轻炎症,延缓/减少肝细胞癌的发展 诱导饮食;在目标2中,通过过表达RIPK3或MLKL将在肝细胞中特异性地诱导坏死性下垂 使用一种新的RIPK3或MLKL敲门小鼠模型,我们开发了一种新的模型来确定是否会在 肝细胞导致肝脏炎症增加,增加了肝细胞癌的进展和发病率。
英文摘要
Project Summary/Abstract The research objective is to identify the source of chronic inflammation in obesity-mediated hepatocellular carcinoma (HCC). Hepatocellular carcinoma (HCC), a major form of liver cancer, is the fourth leading cause of cancer-related deaths worldwide. In recent years, obesity has emerged as the major and independent risk factor for HCC, and HCC is predicted to the third leading cause of cancer-related deaths in the United States by 2030 due to obesity epidemic. Obesity-induced nonalcoholic fatty liver disease (NAFLD), which affects nearly 25% of the US population, is a key driver of HCC in obese individuals. Despite this strong association between obesity and HCC, the mechanisms that drive HCC development in obesity is not clearly understood. Non-resolving chronic inflammation is a major contributor to the development and progression of HCC in obesity and damage associated molecular patterns (DAMPs) are one of the proposed mediators of HCC. Necroptosis is a programmed cell death that has been shown to play a major role in inflammation through the release of DAMPs, which bind to cell surface receptors of immune cells to induce inflammation. In this application, we propose that hepatocyte necroptosis in NAFLD is a key factor in HCC progression. Our preliminary data support the role of necroptosis in HCC, e.g., blocking necroptosis using Ripk3-/- or Mlkl-/- mice reduced hepatic inflammation, infiltration of innate immune cells, and HCC incidence in mice fed a choline deficient-high fat diet (CD-HFD) that do not induce obesity. In a genetic mouse model of spontaneous HCC (Sod1-/- mice) inhibiting necroptosis using necroptosis inhibitor, necrostatin-1s, reduce hepatic necroptosis, inflammation, and pathways mediating HCC development. Based on this, we propose that hepatocyte necroptosis is the major source of hepatic inflammation in the microenvironment where HCC is initiated. We hypothesize that progression of NAFLD to HCC is due to increased inflammation that arises from hepatocyte necroptosis and that preventing necroptosis will reduce inflammation and progression of NAFLD to HCC. This hypothesis will be tested using genetic approaches to block or activate necroptosis in hepatocytes by targeting RIPK3 or MLKL, kinases in the necroptosis pathway, and assessing its effect on inflammation and HCC. In Aim 1, necroptosis will be specifically reduced/blocked in hepatocytes using hepatocyte specific Ripk3 or Mlkl knockout mice, and determine if blocking hepatocyte necroptosis reduces inflammation and delays/reduces HCC development in response to an HCC- inducing diet; In Aim 2, necroptosis will be induced specifically in hepatocytes by overexpressing RIPK3 or MLKL using a novel Ripk3 or Mlkl knockin mouse model we have developed to determine if inducing necroptosis in hepatocytes leads to an increase in liver inflammation and increased progression and incidence of HCC.
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会议论文
Role of necroptosis in inflammation and NAFLD to HCC progression
The Role of Necroptosis in Aging
The Role of Necroptosis in Aging
The Role of Necroptosis in Aging
国内基金
海外基金
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  • 项目类别:
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