Mechanisms controlling pro-inflammatory mast cell functions and implications for chronic liver disease and cancer
控制促炎性肥大细胞功能的机制及其对慢性肝病和癌症的影响
基本信息
- 批准号:452602471
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Mast cells (MCs) are hematopoietic cells of the myeloid lineage, which can take part in processes of innate and adaptive immunity. MCs are best known for their detrimental role in allergy and anaphylaxis, but are also involved in processes of wound healing, angiogenesis, and modulation of tumor growth.Current research has suggested a yet poorly understood function of MCs for initiation and progression of liver disease such as liver fibrosis and hepatocellular carcinoma (HCC). HCC is a primary liver cancer arising as a consequence of chronic liver inflammation, fibrosis and cirrhosis. This pathogenic sequence is driven by soluble mediators such as TGF-β released as a result of an intricate crosstalk by different resident (hepatocytes, hepatic stellate cells) and infiltrating cells (such as MCs). In addition, we have recently demonstrated that the initiation of liver cancer essentially requires the cell cycle mediator Cyclin E1.Our preliminary data points to important contributions of the cell cycle machinery and TGF-β1 signaling pathways for MC biology in general, but also for MC functions in the liver. For instance, we found that Cyclin E1 is also involved in MC differentiation and MC-dependent production of pro-inflammatory cytokines such as interleukin-6. In addition, we found that MC differentiation and it´s effector function is modified by the TGF-β1 co-receptor Endoglin (ENG). Finally, our preliminary data indicated the accumulation of MCs in murine livers with pre-cancerous injury such as advanced fibrosis and tumorous lesions. Altogether, our current knowledge suggests that Cyclin E1- and TGF-β-related signals are required for proper mast cell function and for hepatocarcinogenesis. Yet the underlying mechanisms are poorly understood.The overarching goal of this proposal is therefore a comprehensive analysis of cell cycle and TGF-β related mechanisms in MCs in the context of chronic hepatic diseases. This timely topic will be addressed by a group of experts with outstanding synergistic expertise of the applicants in mast cell biology (Huber), cell cycle regulation (Liedtke), TGF-β signaling (Weiskirchen/Meurer) and animal models of liver disease (Liedtke/Weiskirchen/Meurer).To this end, we propose to thoroughly evaluate the contributions of cell cycle mediators and TGF-β-related signaling molecules during development, differentiation and activation of MCs. Moreover, we will establish novel mouse models, allowing tracking, depleting and modulating MCs, and finally we will identify the contributions of E-type cyclins and ENG in MCs during chronic liver disease and liver cancer development.This project will largely expand our knowledge on mast cell biology and mast cell functions in the diseased liver with the option to identify new targets for the treatment of liver cancer.
肥大细胞(MC)是骨髓系的造血细胞,其可参与先天性和适应性免疫过程。MCs在变态反应和过敏反应中起着重要的作用,但也参与了伤口愈合、血管生成和肿瘤生长的调节等过程,目前的研究表明,MCs在肝纤维化和肝细胞癌(HCC)等肝脏疾病的发生和发展中的作用尚不清楚。HCC是一种原发性肝癌,由于慢性肝脏炎症、纤维化和肝硬化而产生。这种致病序列由可溶性介质驱动,例如TGF-β,其是由于不同驻留细胞(肝细胞、肝星状细胞)和浸润细胞(例如MC)的复杂串扰而释放的。此外,我们最近发现肝癌的发生主要需要细胞周期调节因子Cyclin E1的参与。我们的初步数据表明细胞周期机制和TGF-β1信号通路对MC的生物学和肝脏MC的功能有重要作用。例如,我们发现细胞周期蛋白E1也参与MC分化和MC依赖性促炎细胞因子如白细胞介素-6的产生。此外,我们发现MC分化及其效应器功能被TGF-β1共受体Endoglin(ENG)修饰。最后,我们的初步数据表明MCs在具有癌前损伤如晚期纤维化和肿瘤病变的小鼠肝脏中积累。总之,我们目前的知识表明,细胞周期蛋白E1和TGF-β相关信号是肥大细胞正常功能和肝癌发生所必需的。然而,其潜在的机制知之甚少,因此,本提案的总体目标是在慢性肝病的背景下,对MC中的细胞周期和TGF-β相关机制进行全面分析。这一及时的主题将由一组在肥大细胞生物学(Huber)、细胞周期调控(Liedtke)、TGF-β信号传导(TGF-β)(Weiskirchen/Meurer)和肝病动物模型(Liedtke/Weiskirchen/Meurer)。为此,我们建议彻底评估细胞周期介质和TGF-β相关信号分子在发育过程中的作用,MC的分化和活化。此外,我们将建立新型小鼠模型,追踪、消耗和调节MC,并最终确定E型细胞周期蛋白和ENG在MC中在慢性肝病和肝癌发展过程中的作用。该项目将极大地扩展我们对肥大细胞生物学和肥大细胞在病变肝脏中功能的认识,并为肝癌的治疗找到新的靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Professor Dr. Michael Huber其他文献
Professor Dr. Michael Huber的其他文献
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{{ truncateString('Professor Dr. Michael Huber', 18)}}的其他基金
Control of FceRI-mediated mast cell activation by the functional interplay of membrane-organizing and cytoskeleton-interacting proteins
通过膜组织蛋白和细胞骨架相互作用蛋白的功能相互作用控制 Fceï¥RI 介导的肥大细胞激活
- 批准号:
406108376 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Research Grants
Quantification, Administrative Capacity and Democracy
量化、行政能力和民主
- 批准号:
278853747 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Research Grants
Supra-optimal FcepsilonRI activation – a condition to identify suppressive mechanisms in mast cell activation
超优化 FcepsilonRI 激活 â 是识别肥大细胞激活抑制机制的条件
- 批准号:
253541349 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Research Grants
The inositol phosphatase SHIP1 as the regulator of the physiological mast cell response
肌醇磷酸酶 SHIP1 作为生理肥大细胞反应的调节剂
- 批准号:
124579250 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Priority Programmes
Discrete Structures in Combinatorics, Information Theory and the Theory of Algorithms
组合学、信息论和算法理论中的离散结构
- 批准号:
39993490 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Heisenberg Fellowships
Die Rolle FcepsilonR1-interagierender Proteine für die Allergen/Antigenvermittelte Aktivierung von Mastzellen
FcepsilonR1相互作用蛋白在过敏原/抗原介导的肥大细胞激活中的作用
- 批准号:
48288264 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Research Grants
Regulation und Funktion des Transkriptionsfaktors Krüppel-like factor 2 (KLF2) in Mastzellen
肥大细胞中转录因子 Krüppel 样因子 2 (KLF2) 的调节和功能
- 批准号:
5452086 - 财政年份:2005
- 资助金额:
-- - 项目类别:
Research Grants
Native Analyse von P13K-enthaltenden Proteinkomplexen im Rahmen der Aktivierung von Mastzellen
肥大细胞激活背景下含 P13K 蛋白复合物的天然分析
- 批准号:
5404148 - 财政年份:2003
- 资助金额:
-- - 项目类别:
Research Grants
Untersuchung von Mastzellfunktionen im molekularen Spannungsfeld zwischen PKC Isotypen und der Inositolphposphatase SHIP
肥大细胞在 PKC 同种型和肌醇磷酸酶 SHIP 之间张力分子场中的功能研究
- 批准号:
5386021 - 财政年份:2002
- 资助金额:
-- - 项目类别:
Research Grants
Construction and classification of flag-transitive Steiner designs
标志传递斯坦纳设计的构造和分类
- 批准号:
5363953 - 财政年份:2002
- 资助金额:
-- - 项目类别:
Research Grants
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