SR-A1在动脉粥样硬化发病学中精准作用的研究：类人化仓鼠模型的构建和应用

Atherosclerosis (AS), which is the main cause of coronary heart disease and cerebral infarction, is a chronic disease that occurs in the vascular wall. AS research can not be carried out without appropriate animal models, and the ideal animal model of disease should be able to demonstrate similar metabolic abnormalities and pathological processes with human diseases. The mouse AS model are built on the basis of gene modified, So can not well reflect the natural course of disease in humans. The role of A1 class a scavenger receptor (SR-A1) in the development of AS is a typical example. The hamster has gradually become an important new model of diet induced AS animal. Compared with other rodents, hamsters are more similar to the human in lipid metabolism. Therefore, this project by using CRISPR/CAS9 system to construct SR-A1 gene knock hamster AS model. In this project, we will investigate the effect of SR-A mediated change in macrophage activities impacts AS. The aim of our study is to elucidate molecular mechanisms underlying macrophage activities in AS. This study will be helpful to provide new therapeutic targets for AS.

动脉粥样硬化(AS)是发生于血管壁的慢性疾病。开展AS研究离不开合适的动物模型，而理想的疾病动物模型应该能够表现出与人类疾病相似的代谢异常和病理过程。由于小鼠AS模型都是建立在一定的基因修饰的基础上，并不能够很好地反映人类疾病的自然过程，以小鼠为模型得到的实验结果有时并不完全一致，A1类清道夫受体（SR-A1）在AS发生发展中的作用研究就是一个典型的例子。从上世纪80年代开始，仓鼠逐渐成为研究饮食诱导的AS的重要新的模式动物。相比于其他一些啮齿类动物，仓鼠在脂代谢方面与人类更为接近。为此，本项目拟应用CRISPR/CAS9系统建立SR-A1基因敲除仓鼠模型，并通过高脂饮食诱导形成AS，在此基础上深入开展SR-A1对于血管壁中巨噬细胞生物学活性调节作用的研究，这不仅有助于明确SR-A1在AS中的作用，更对于深刻揭示巨噬细胞与AS的内在联系全面认识AS的发生发展规律具有重要意义。

炎症反应、脂质积聚和细胞凋亡是AS的基本病理过程，为深刻洞悉AS中炎症反应、脂质积聚和细胞凋亡等重要发病环节的分子调控机制奠定了坚实基础。为此，本项目拟应用CRISPR/CAS9系统建立SR-A1基因敲除仓鼠模型，并通过饮食诱导形成AS，在此基础上深入开展SR-A1对于血管壁中巨噬细胞生物学活性调节作用的研究。本项研究不仅有助于明确SR-A1在AS中的作用，解决长期困惑学界的一个重要科学问题，更对于深刻揭示巨噬细胞与AS的内在联系、全面认识AS的发生发展规律具有重要意义。本课题取得重大进展，已发表标注有项目编号81670418的SCI论文8篇，获得国家发明专利2项，获得2019年江苏省科技进步二等奖1项。