Molecular, functional and micro-morphological imaging of bone metastases in vivo

骨微环境的复杂性和骨转移过程中相互作用的多种细胞类型需要开发适用于体内这些过程的多模态分子，功能和微形态成像的技术。我们将测试的假设是否可以采用成骨细胞，破骨细胞和肿瘤细胞相互作用的分子标记物，以允许纵向监测这些细胞在骨转移过程中的微观结构水平。光学报告基因置于成骨细胞组织特异性启动子α1（I）-胶原蛋白的控制下，将允许标记免疫缺陷小鼠品系中的成骨细胞谱系细胞。将开发基于反映成骨细胞诱导的基质沉积、破骨细胞数量（αvβ3整联蛋白）和功能（组织蛋白酶K表达）的荧光标记物的成像方法，以研究肿瘤-骨相互作用，例如Dickkopf-1。将优化结合荧光分子断层扫描（FMT）和微型计算机断层扫描（micro-CT）的多模态成像，以进行定量纵向评价。我们的工作将验证可量化FMT/微型CT标记物和方法的强大基本设备，这些标记物和方法有可能对合作伙伴项目中表征的肿瘤-骨骼相互作用特异性目标进行成像。这样的方法将增强非侵入性监测也响应于治疗的转移过程的能力。

The complexity of the bone microenvironment and the multitude of cell types interacting with each other during skeletal metastasis necessitate the development of technologies suited for multimodal molecular, functional and micro-morphological imaging of these processes in vivo. We will test the hypothesis whether molecular markers specific for osteoblasts, osteoclasts and tumor cell interaction can be employed to allow for longitudinal monitoring of these cells during skeletal metastasis at the microstructural level. An optical reporter gene placed under the control of the osteoblast tissue-specific promoter, α1(I)-collagen, will allow to label cells of the osteoblastic lineage in an immunodeficient mouse strain. Imaging methods based on fluorescent markers reflecting osteoblast induced matrix apposition, osteoclast number (αvβ3 integrin) and function (cathepsin K expression) will be developed to study tumor-bone interaction, e.g. with regard to Dickkopf-1. Multi-modality imaging combining fluorescent molecular tomography (FMT) and micro-computed tomography (micro-CT) will be optimized for quantitative longitudinal evaluation. Our work will result in validation of a robust basic armamentarium of quantifiable FMT/micro-CT markers and methods with potential to image tumor-bone interaction-specific targets which are characterized in partner projects. Such methods will augment the ability to non-invasively monitor metastatic processes also in response to treatment.