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The impact of Cyclin E1 in alcohol-induced organ disease and carcinogenesis within the Gut-liver axis

Cyclin E1 对酒精诱发的器官疾病和肠肝轴癌变的影响

基本信息

批准号：
334239546
负责人：
Dr. Yulia Nevzorova, Ph.D.
金额：
--
依托单位：
Klinik für Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin (Med. Klinik III)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/334239546?language=en
关键词：
impact Cyclin E1 alcohol induced

项目摘要

The impaired interaction between gut and liver is a frequent cause of various liver diseases. Alterations in the permeability of the intestinal epithelium lead to the intensive passage of intestinal microflora followed by hepatic inflammation or end-stage carcinogenesis. In previous work, it was shown that inhibition of the cell cycle mediator Cyclin E1 has a protective effect in an established mouse model of liver tumorigenesis. However, the absence of Cyclin E1 caused increased liver and gut epithelium injury after chronic alcohol exposure. The main aim of the current proposal is to elucidate the function of Cyclin E1 in the alcohol-induced tumorigenesis in the intestine and in the liver. To this end, an in-depth analysis of the consequences of complete Cyclin E1 depletion in mice after chronic alcohol exposure will be performed in the gut-liver axis, and effector cells will be identified. Additionally, using murine models, it will be examined whether inhibition of Cyclin E1 is protective against the development of alcohol-induced liver or colon cancer. Finally, the clinical translationality of our preclinical research will be explored by determining the prevalence of Cyclin E disorders in patients with alcohol-induced liver and colon cancer. In summary, this study is of utmost interest since it will be able to unveil whether the inhibition of Cyclin E1 provides a novel therapeutic option for the treatment of alcohol-related cancers.

肠道和肝脏之间的相互作用受损是各种肝脏疾病的常见原因。肠上皮通透性的改变导致肠道微生物密集通过，随后是肝脏炎症或终末期癌变。在以前的工作中，它表明，抑制细胞周期介质细胞周期蛋白E1在建立的小鼠模型的肝脏肿瘤发生具有保护作用。然而，细胞周期蛋白E1的缺乏导致慢性酒精暴露后肝和肠上皮细胞损伤增加。目前的建议的主要目的是阐明细胞周期蛋白E1在酒精诱导的肿瘤发生在肠道和肝脏中的功能。为此，将在肠-肝轴中对慢性酒精暴露后小鼠中细胞周期蛋白E1完全耗尽的后果进行深入分析，并将鉴定效应细胞。此外，使用鼠模型，将检查细胞周期蛋白E1的抑制是否对酒精诱导的肝癌或结肠癌的发展具有保护作用。最后，我们的临床前研究将通过确定酒精诱导的肝癌和结肠癌患者中细胞周期蛋白E紊乱的患病率来探索临床的可行性。总之，这项研究是最感兴趣的，因为它将能够揭示细胞周期蛋白E1的抑制是否为酒精相关癌症的治疗提供了一种新的治疗选择。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

DOI：
10.1073/pnas.1807155115
发表时间：
2018-09-11
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Sonntag, Roland;Giebeler, Nives;Liedtke, Christian
通讯作者：
Liedtke, Christian

Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro