SDSSD多肽靶向促进成骨细胞分化在颌骨缺损修复中的作用及机制研究

The key point of tissue respiration of mandibular defect caused by tumor, trauma and others is how to accelerate new bone formation. If osteoblast-targeting delivery could be achieved during bone repair, both side effects and treatment costs will be reduced. But, how to achieve osteoblast-targeting is still a key issue. Our preliminary study have demonstrated that the amino acid sequence SDSSD from DSPP exhibited good osteoblast-targeting property in long bone. In addition, SDSSD could enhance the mineralization of osteoblasts in vitro. This study concerns whether SDSSD could effectively target mandibular osteoblasts, promote their differentiation, and facilitate mandibular defect respiration. We investigate the role of SDSSD in improving bone increase, osteoblast targeting and osteoblast differentiation. Protein chemistry method was employed to identify the targeted membrane proteins. To figure out the mechanism of osteoblast targeting and promoting osteoblast differentiation, the key mRNA and miRNA regulated by SDSSD was analyzed. Then, through the animal model of mandibular defects, role of SDSSD in accelerating osteogenesis will be discovered. This study will provide a theoretical basis for the use of SDSSD to promote the repair of mandibular defects.

肿瘤、外伤等原因造成的颌骨缺损修复的关键问题是如何加快缺损区的新骨生成。在骨修复过程中，骨组织靶向给药将明显提高成骨效率、减少副作用和治疗成本，但如何实现成骨细胞靶向仍是关键前题。我们前期研究发现一段源自于牙本质涎磷蛋白的多肽片段SDSSD，在长骨的骨髓腔中能够特异性结合成骨细胞。本研究关注SDSSD多肽能否靶向促成骨细胞分化，实现颌骨缺损的加速修复。首先通过细胞和动物实验研究SDSSD在颌骨中的成骨细胞靶向性及促骨生成能力；蛋白质化学方法筛选其靶向结合的胞膜蛋白；通过转录组测序筛选SDSSD调节的关键mRNA和miRNA，并对上述基因表达进行干预来探究SDSSD促成骨细胞分化的具体分子机制。最后通过颌骨缺损疾病模型研究SDSSD在加速颌骨修复中的作用。本研究将为利用SDSSD多肽靶向促进颌骨缺损修复提供理论依据。

肽类药物被公认为具有高选择性、高效和良好的患者耐受性，而多肽类药物（寡肽）因其高生物利用度和低合成成本受到越来越多的关注。前期研究表明，牙本质基质蛋白、牙本质涎磷蛋白等细胞外基质蛋白具有良好的促成骨作用，那么如何通过已知蛋白设计多肽类药物的功能序列是多肽分子成为候选药物的主要瓶颈。课题组设计开发了具有深度学习功能的人工智能筛选程序，得到了具有成骨潜力的多肽序列SESSE。实验结果显示，SESSE肽具有良好的成骨靶向性、促成骨能力及生物安全性。在类种植体、骨质疏松和骨折等骨病模型中表现出了一定的促成骨功能。同时结合动物及体外实验探讨了SESSE肽对促进骨髓间充质干细胞（BMSC）成骨分化的关键机制。研究表明SESSE肽在临床转化方向具有良好的应用前景，并为多肽有效序列的筛选提供了新的思路和方法。