自噬相关蛋白SVIP激活破骨细胞促布鲁氏菌性关节炎的机理研究

Brucella infection with high incidence in Inner Mongolia, Brucellar arthritis is one of the common complications, the quality life of patients was seriously affected due to the limitation of clinical treatment, we need to clarify its mechanism for the development of clinical treatment drugs. Studies have shown that the Brucella infection can promote differentiation of osteoclasts and the activity of osteoclasts, which could lead to osteolysis and Bone resorption, but the detailed molecular mechanism is still unclear. The pre-experiment showed that Brucella infected macrophages, which could promote the differentiation from macrophages to osteoclasts, and the expression of SVIP was up-regulated. The literature found that SVIP was associated with the formation of intracellular vesicle; researches have also showen that vesicles have the function of acid secretion, which could promote the formation of actin ring. Based on the results of pre-experiment and literature research, we hypothesize: Brucella infection promoted the formation of actin ring through the autophagy-related protein SVIP, which could lead to differentiation from macrophages to osteoclasts. To validate the hypothesis, osteoclast differentiation of macrophages model was used to detect the regulation of SVIP by Brucella, and SVIP promoted the formation of actin ring, which lead to differentiation of osteoclasts. Finally, this mechanism will be validated by animal and population samples of Brucella infection in Inner Mongolia. The development of project provides the important references for Brucellar arthritis prevention and control.

布鲁氏菌感染在我国内蒙古地区高发，布鲁氏菌关节炎是其常见并发症，临床治疗手段有限，病人生活质量严重受影响，为研发临床治疗药物急需阐明其机理。研究表明布鲁氏菌感染促进破骨细胞的分化和活性，导致骨的溶解和吸收，但具体分子机理不明。前期预实验显示布鲁氏菌感染巨噬细胞后，可促巨噬细胞分化为破骨细胞，同时检测到自噬相关蛋白SVIP的表达上调。查询文献发现SVIP与细胞内囊泡形成相关；也有研究表明囊泡具有泌酸的功能，可促进破骨细胞肌动蛋白环的形成。根据预实验及文献查询结果，提出假设：布菌感染通过自噬相关蛋白SVIP促进肌动蛋白环的形成导致巨噬细胞向破骨细胞分化。为验证假设，拟采用巨噬细胞破骨分化模型，检测布鲁氏菌对SVIP的调控，SVIP促肌动蛋白环形成导致破骨分化的功能。最后通过内蒙古地区布鲁氏菌感染现场的动物和人群样本来验证这一机理。本项目的开展为布鲁氏菌性关节炎的预防和控制提供重要的理论依据。

布鲁氏菌病在内蒙古地区高发，内蒙古地区布病的发病率为全国发病率10倍左右，尤以锡林郭勒盟地区布病最为严重。布鲁氏菌病慢性化率较高，其中布鲁氏菌关节炎是慢性布鲁氏菌病最常见的并发症，布鲁氏菌关节炎临床治疗手段有限，病人的生活质量受到严重影响，为研发临床治疗药物急需阐明其机理。前期研究结果显示：布鲁氏菌感染可促进破骨细胞的分化和活化，导致骨的溶解和吸收，但具体分子机理不明。本项目为布鲁氏菌感染并发关节损害的治疗提供临床依据，同时为采取更好地预防和控制布鲁氏菌性关节炎的措施提供新的理论支持。.课题组整合了近10年内蒙古地区人群布鲁氏菌病的流行数据，开展现场流行病学专项调查，收集布鲁氏菌病患者的患病情况、诊疗转归情况及其生物样本，共收集了348例布鲁氏菌病感染患者（包括262例布鲁氏菌性关节炎患者）的详细数据资料，建立了内蒙古地区布鲁氏菌病数据库。前期人群布鲁氏菌病数据分析结果显示：尽管内蒙古地区人布鲁氏菌病总体发病率呈下降趋势，但年发病率仍居于较高水平（29.68–77.67/10万）；40-59岁、男性、农牧民的布病发病率较高；锡林郭勒盟是高风险地区；宿主主要以羊、牛为主；经济水平低、医疗水平差的地区，布病患病率较高；布病发病风险还与当地的平均气温呈负相关，与平均风速呈正相关。此研究结果发表一篇文章：《Spatiotemporal Distribution of Human Brucellosis in Inner Mongolia, China, in 2010-2015, and Influencing Factors》。专项调查的348例布病患者的资料分析结果显示，布鲁氏菌病患者治愈后的复发率为18.18%，慢性化率为30.46%。现有的生物样本已完成前期处理工作，准备实施实验室检测及生物信息学分析。.布病传播途径复杂，人群疾病负担较重，特别是布鲁氏菌病关节炎，发病率高、致残率高、生活质量差，通过研究布鲁氏菌感染后关节炎的发病机制，可以为布鲁氏菌性关节炎的预防、控制以及临床治疗提供新的实验室数据和理论依据。