基于骨质疏松模型猴的大麻素受体治疗靶点的可视化研究

Cannabinoid receptors (CB) are closely related to osteoporosis (OP), and become a new strategy for bone-targeted therapy. The research of CB in bone plays a critical role in the evaluation of OP drug efficacy, individualized treatment, as well as the development of new drugs. However, most previous studies were based on OP mouse models, whose skeletal structures were dramatically different with those in humans. Besides, there is no quantitative data in vivo, which limited the clinical translation of CB-targeted OP therapeutic strategies. In the early stage, we have established the multimodal imaging platform for rhesus macaques bone study, including structural imaging and PET/CT-MR molecular/functional imaging. The digital information of rhesus bone can be monitored and obtained in real time through non-invasive imaging technologies. In this project, we plan to take the osteoporosis rhesus models as the research subjects to acquire the bone structural information by means of DXA, QCT and QMR, and real-time quantitative analysis of CB receptors in different experimental conditions by PET imaging. In addition, the biochemical indicators of bone metabolism, histopathological examination and micro-CT in vitro would be conducted to support the in vivo imaging data, and to illustrate the quantitative relationship between CB receptors and osteoporosis. This research will provide a scientific basis for the CB-targeted osteoporosis therapy.

大麻素受体与骨质疏松症（Osteoporosis, OP）密切相关，成为骨靶向治疗的新策略，对OP药物疗效评价、个体化治疗及靶向型新药开发等意义重大，但目前研究结果均基于啮齿类动物模型，其骨骼结构与人差异较大且无活体定量数据信息，限制了大麻素受体靶向OP治疗策略的临床转化。申请团队前期以恒河猴为研究对象，建立了形态结构影像及PET/CT-MR分子功能影像多模态成像平台，可通过无创可视化手段实时监测骨骼结构，获取数字化信息。本项目中，我们拟以恒河猴骨质疏松模型为研究对象，通过DXA、QCT、QMR等方法获取骨结构影像数字化信息，利用靶向大麻素受体的PET分子影像活体实时定量分析受体的分布及含量变化，同时结合血清骨代谢生化指标、骨活检标本组织病理及离体microCT等方法对活体成像数据提供支持，建立受体靶向骨质疏松疾病的定量关系，为基于大麻素受体靶向治疗骨质疏松疾病建立研究方法和提供科学依据。

在项目基金的支持下，本课题组充分利用组内的资源和优势，建立了完善的食蟹猴骨DXA、QCT、PET/CT-MRI影像研究平台，首次构建了基于大样本长年龄跨度的食蟹猴骨密度和骨代谢数据的数字化信息库，通过不同角度综合观察食蟹猴骨骼生长发育以及随年龄变化情况。建立了新型PET正电子示踪剂放射化学标记与研发平台，完成了特异性靶向内源性大麻素受体1（CB1R）的PET探针[11C]OMAR的自动化合成，建立了基于PET放射性药物的非人灵长类动物研究的药代动力学分析平台，并扩展应用于其他新型PET正电子示踪剂研发和临床转化研究；首次建立了非人灵长类动物脑PET-MRI影像分析模板；基于大样本量、长年龄跨度的食蟹猴18F-FDG PET/CT-MRI影像数据建立了首创性的食蟹猴多模态脑影像发育模板，并对猴脑体积和糖代谢进行年龄相关的定量分析。.在青年食蟹猴和老年骨质疏松食蟹猴的PET/CT-MRI的可视化研究中，首次发现在骨质疏松食蟹猴的腰椎和脑中内源性大麻素受体的表达上调，提示可能存在“脑-骨轴”的调节；使用拮抗剂也延缓了骨质疏松模型鼠的骨流失。为建立与骨质疏松症的定量关系奠定了基础，对深入了解内源性大麻素受体在骨质疏松症发病机制中的作用，开发针对骨质疏松症的药物具有重要意义。.本项目是目前涉及样本最大，跨年龄段最长的，系统性地对食蟹猴的骨密度与骨代谢、猴脑发育与糖代谢研究，这将对食蟹猴的骨质疏松和脑神经疾病的研究奠定基础。我们建立了骨代谢数字化信息库、食蟹猴脑影像标准化分析工具，为非人灵长类动物多模式分子影像研究提供技术支撑。