广西巴马小型猪骨质疏松模型

Osteoporosis is characterised by low bone mass and a microarchitectural deterioration of the bone tissue. Due to the high mortality and morbidity, osteoporosis-related fractures have become a formidable public health threat. However, currently used animal model of osteoporosis for scientific research are mainly established on small animals，which is very different with human and restrictive in the translational clinical research. The existing animal models can not simulate pregnancy and lactation-associated osteoporosis, and also fail to explore the impact of osteoporosis on the whole system in the whole life cycle..BA-MA minipigs are independently cultivated strains in our country and are similar to humans in many systems. Our previous study shows that ovariectomized BA-MA minipigs can well simulate postmenopausal osteoporosis, but the relevant data is little, and this model has not yet been fully recognized internationally. The conditions and equipment for modeling need to be further optimized..This study intends to take the BA-MA minipigs as the research object：①based on the physiological data of its whole lifecycle， we construct the ovariectomized minipig model to simulate postmenopausal osteoporosis and build PLO minipigs model by low calcium diet to imitate pregnancy and lactation- associated osteoporosis; ②use the postpartum minipigs to construct the postmenopausal osteoporosis model, which closely imitates human disease; ③based on the similarity of the multiple systems between minipigs and human beings, we explore the influence of pregnancy and lactation-associated osteoporosis on diabetes and postpartum depression. This study is conducive to clinical transformation and the development of native experimental animals.

随着人口老龄化，骨质疏松危害越来越大，目前常用的绝经后骨质疏松（PMO）小动物模型，与人类差异大，限制了临床转化和药品器械研发；随着生育政策放开，妊娠哺乳期骨质疏松（PLO）的危害不容忽视，但PLO动物模型匮乏。构建理想的骨质疏松大动物模型迫在眉睫。.巴马小型猪是我国自主培育的品系，许多系统与人类相似。我们前期证实巴马小型猪去卵巢能模拟PMO，但相关数据少，尚未获得国际充分认可。本课题以巴马小型猪为研究对象，采集其生命全周期的骨代谢数据；去卵巢构建PMO小型猪模型；妊娠哺乳期钙限制饮食构建PLO小型猪模型；观察PLO对糖代谢紊乱、产后抑郁的影响，实现“一模多病”；分别在未孕产、经孕产和PLO小型猪基础上，去卵巢构建真实模拟人类骨质疏松过程的PMO大动物模型。.本课题对探索骨质疏松发生和发展机理、发现药物新靶点以及临床前评价等具有重要的理论价值和临床意义。

项目背景：.骨质疏松性骨折发病率高、致残率高，课题组前期研究发现，髋部骨折在2012-2016绝对数量增长了约4倍；椎体骨折发病率连续5年攀升，绝对数量增长5.82倍；不仅如此，脆性骨折的医疗支出巨大，造成沉重负担。随着中国社会人口老龄化，骨质疏松的危害与日俱增，防治骨质疏松迫在眉睫。.“工欲善其事，必先利其器”，研究骨质疏松的机制需要有良好的动物模型，目前常见的有鼠、兔、羊、犬、猪等；常用的方法有去卵巢法、药物诱导法、废用法和营养缺陷法。但是各类模型各有优缺点。同时，骨质疏松新药的动物试验和新型医疗器械的临床前评价也需要稳定可靠的大动物模型。.目前，多数药物、器械研发来自国外的研究，国内研究多是基于国外学者建立的模型,但大动物进出口存在壁垒，同一物种不同品系之间存在生理差异；因此，建立基于本土大动物的人类疾病模型平台刻不容缓。广西巴马小型猪是我国自主培育出的品系，具有遗传稳定、多产、体重较小等特征，不但心血管系统、消化系统、营养需要等与人相似，而且骨骼发育以及矿物质代谢也与人相近，具有成为骨质疏松疾病模型的潜力。.主要研究内容：.基于巴马小型猪的骨质疏松模型的制备与评价.重要结果：.10月龄巴马小型猪去卵巢后18个月后，第二腰椎、第三腰椎、第四腰椎和双侧股骨颈的骨密度明显低于对照组；micro-CT结果提示，去卵巢组小型猪的骨微结构比对照组疏松；骨转换指标提示去卵巢后，骨转换加快。.关键数据：.巴马小型猪腰椎和双侧髋部的动态骨密度、尾椎骨活检标本micro-CT评价、骨转换血清学指标.科学意义：.收集巴马小型猪育龄期正常生理数据以及去卵巢小型猪的生理数据，明确雌激素对巴马小型猪骨量水平的影响，为绝经后骨质疏松模型的构建提供基线数据和评价依据。成功构建基于巴马小型猪的骨质疏松模型是对建立中国本土的骨质疏松大动物疾病模型的重要补充；能够为骨质疏松药品、医疗器械研发，提供可靠、有效、便捷的疾病模型；为中国医药卫生科技创新的发展提供坚实基础。