Studies of the functions of TGFBI in bone homeostasis and cancer development

TGFBI 在骨稳态和癌症发展中的功能研究

• 批准号: 194110679
• 负责人: Dr. Jochen Schulze
• 金额: --
• 依托单位: Universitätsklinik für Dermatologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/194110679?language=en
• 关键词: Studies; functions; TGFBI; bone; homeostasis

The extracellular matrix (ECM) is a major part of the body’s connective tissues like bone and cartilage. Thus several mutations affecting proteins of the ECM are linked to human diseases. For example Osteogenesis imperfecta is characterized by a reduced bone mineral density and biomechanical instability. Additionally the ECM has pivotal functions in diverse types of cancer, since interactions of cancer cells with the ECM influence migration, proliferation, survival and apoptosis of cancer cells. I plan to analyze the functions of the ECM protein TGFBI (or βIg-h3), a putative target gene of the AP- 1 transcription factor FOS in bone-forming osteoblasts and myocytes. By characterizing the phenotype of mice with osteoblast-specific loss of function of Tgfbi and mice that inducibly overexpress Tgfbi in osteoblasts, the physiological role of TGFBI in bone homeostasis will be investigated. Fos overexpression under the control of the H2 promoter results in the development of osteosarcoma (OS) in mice. Therefore the role of Tgfbi as a target gene of Fos will be genetically adressed in this context. Human OS cell lines and human tumor biopsies will be used to elucidate the function of FOS and TGFBI and to validate the data obtained in mouse models.Since Fos can also function as a tumor suppressor in specific cellular contexts, the second aim of the project is to investigate the function of Tgfbi as a potential tumor suppressor gene in a Fos-dependent mouse model of Rhabdomyosarcoma (RMS). The goal will be first to establish an improved model of RMS in mice by deleting Fos and p53 specifically in muscle cells and to investigate the relevance of TGFBI in this setting and in human RMS. I plan to perform in vitro analyses of human RMS cells after stable knock-down or over-expression of FOS and TGFBI. Human patient material will also be analyzed.

细胞外基质（ECM）是人体结缔组织（如骨和软骨）的主要组成部分。因此，影响ECM蛋白质的几种突变与人类疾病有关。例如，骨生成障碍的特征在于骨矿物质密度降低和生物力学不稳定。此外，ECM在不同类型的癌症中具有关键功能，因为癌细胞与ECM的相互作用影响癌细胞的迁移、增殖、存活和凋亡。我计划分析ECM蛋白TGFBI（或βIg-h3）的功能，TGFBI是骨形成成骨细胞和肌细胞中AP- 1转录因子FOS的假定靶基因。通过表征具有成骨细胞特异性Tgfbi功能丧失的小鼠和在成骨细胞中诱导性过表达Tgfbi的小鼠的表型，将研究TGfbi在骨稳态中的生理作用。在H2启动子控制下的Fos过表达导致小鼠骨肉瘤（OS）的发展。因此，Tgfbi作为Fos靶基因的作用将在此背景下从遗传学角度进行探讨。由于Fos在特定的细胞环境中也能发挥抑癌基因的作用，本项目的第二个目的是在Fos依赖的横纹肌肉瘤（RMS）小鼠模型中研究Tgfbi作为潜在抑癌基因的功能。我们的目标将是首先建立一个改进的RMS模型，在小鼠中删除Fos和p53，特别是在肌肉细胞和研究TGFBI在这种情况下，在人类RMS的相关性。我计划在稳定敲低或过表达FOS和TGFBI后对人RMS细胞进行体外分析。还将分析人类患者材料。