Biology of Prion Protein and the TSE Diseases

在2008财年，我们使用趋化因子受体基因CCR 1遗传缺陷的小鼠研究了朊病毒/TSE疾病的致病过程。这些小鼠在羊瘙痒病感染后比野生型（WT）小鼠更快地死亡，但与疾病相关的蛋白酶抗性PrP水平在CCR 1敲除（KO）小鼠中反而更低。感染的KO小鼠上调了CCL 3（CCR 1配体）和CCR 5（CCL 3特异性受体）。 感染的KO和WT小鼠均上调了CCR 5介导的信号传导，涉及星形胶质细胞中Erk 1/2的激活;然而，KO小鼠中的激活较早，表明在发病机制中起作用。在这两种小鼠品系中，Erk 1/2通路的激活可能导致星形胶质细胞功能障碍，从而导致神经变性。

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.