Biology of Prion Protein and the TSE Diseases

在2008财年，我们利用趋化因子受体基因CCR1基因缺陷的小鼠，研究了Pron/TSE疾病的致病过程。这些小鼠在感染瘙痒病后比野生型(WT)小鼠死亡更快，但CCR1基因敲除(KO)小鼠的疾病相关蛋白酶抗性PrP水平却出奇地低。感染的KO小鼠CCL3和CCR5表达上调，CCR3是CCR1的配体，CCR5是CCL3的特异性受体。感染KO和WT的小鼠都有CCR5介导的信号上调，涉及到星形胶质细胞中ERK1/2的激活；然而，KO小鼠的激活更早，表明在发病机制中发挥了作用。在这两个品系的小鼠中，ERK1/2通路的激活可能会导致星形胶质细胞功能障碍，导致神经变性。

In FY08 we studied the pathogenic process involved in prion/TSE diseases by using mice genetically deficient in a chemokine receptor gene, CCR1. These mice succumbed more rapidly than wild-type (WT) mice following scrapie infection, but the levels of the disease-associated protease-resistant PrP were paradoxically lower in CCR1 knockout (KO) mice. Infected KO mice had upregulation of CCL3, a CCR1 ligand, and CCR5, a receptor with specificity for CCL3. Both infected KO and WT mice had upregulation of CCR5-mediated signaling involving activation of Erk1/2 in astrocytes; however, activation was earlier in KO mice suggesting a role in pathogenesis. In both mouse strains activation of the Erk1/2 pathway may lead to astrocyte dysfunction resulting in neurodegeneration.