Scara1受体在小胶质细胞吞噬和清除PrPSc中作用机制的研究

众所周知，病原因子PrPSc和淀粉样蛋白的蓄积是朊蛋白疾病的重要病理特征。已有研究证实，激活的小胶质细胞表面表达大量的受体,可以介导细胞粘着和胞饮作用。然而，参与小胶质细胞吞噬和清除PrPSc的受体及其作用机制尚不清楚。本课题以清道夫受体A族（Scara1）成员可能作为小胶质细胞吞噬和清除PrPSc和淀粉样蛋白的关键受体为切入点，通过shRNA干扰技术建立Scara1基因缺失的小胶质细胞模型,利用基因重组技术建立Scara1基因缺失小鼠，用于体内实验研究模型。通过药理方式和构建真核表达质粒，建立Scara1基因的过表达模型。系统的研究Scara1基因的缺失或过表达对小胶质细胞吞噬和清除PrPSc和淀粉样蛋白能力的影响，进而阐明小胶质细胞对PrPSc的吞噬和清除机制，为朊蛋白疾病的治疗靶位点筛选提供理论依据和技术支持。

As we known ，the pathologic features that characterize prion diseases are the protease-resisitant pathogenic form of prion protein-PrPSc and the accumulation of fibrils or amyloid plaques . As macrophages of the central nervous system, the phagocytic capacity of microglia is well recognized, and it is possible that the activated microglia express several receptors involving in the adhension of cells and phagocytosis. However, the mechanism of microglial cells in gulfing and clearing PrPSc and fibrils or amyloid plaques is unclear. We hypothesis that the scavenger receptor Scara1 expressed on myeloid cells may as a key receptor in clearance of PrPSc and fibrils or amyloid plaques. To determine the role of Scara1 in this process, we use shRNA technique to construct a Scara1-deficient microglial cell line and gene recombination technology to establish a Scara1-deficient mice model in vitro and in vivo, respectively .In contrast, we construct the overexpression model of Scara1 by pharmacological upregulation as well as construction of Scara1 eukaryotic expression plasmid. The systematic study of the deficiency or overexpression of Scara1 on the influence for the phagocytic and scavenging capacity of microglia to PrPSc and fibrils or amyloid plaques illustrates the phagocytic mechanism of microglia in removing PrPSc and fibrils or amyloid plaques, which may be important for the basic regulatory mechanism of prion diseases and associated neurodegenerative diseases and provides a novel therapeutic target for prion diseases in vivo .