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Clarification of the protective mechanisms of pregnancy to the phenotype of saposin A deficient mice, mouse model for a late-onset, chronic form of globoid cell leukodystrophy

澄清妊娠对 saposin A 缺陷小鼠表型的保护机制，迟发性慢性球状细胞脑白质营养不良小鼠模型

基本信息

批准号：
14370247
负责人：
KURODA Yasuhiro
金额：
$ 8.96万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

We have generated a new mouse model for a late-onset, chronic form of globoid cell leukodysirophy (GLD, Krabbe disease), by introducing a mutation (C106F) into the saposin A domain of the sphingolipid activator protein gene (prosaposin). Most interestingly, we found significant clinical and pathological improvements in the pregnant saposin A deficient (sap A^<1/1>) mice. We also found that high level of estrogen (17β-estrdiol) supplementation could substantially duplicate the phenomena of pregnancy in sap-A^<-/-> mice. Based on these evidences, we hypothesize that higher female sex hormones such as estrogen during pregnancy can suppress the activation of microglia or macrophages and prevent them producing detrimental molecules in the demyelinating brain lesions of sap-A^<-/->mice. To evaluate ibis hypothesis, we analyzed the possible effect of gender, pregnancy or female sex hor lone supplementation to the mRNA expression of variable cytokines and cytokine receptors in the brain of sap-A^<-/-> mice. Then we found dramatic upregulation of chemokines and cytokines in the brain of sap-A^</-> mice, especially on Rantes, MIP-1β, MIP-1α, MIP-2, MCP-1 aid TNF-α. These upregulations of Rantes, MIP-1(3, MIP-1α, MIP-2 and MCP-1 were suppressed in female or pregnant sap-A^<-/-> mice brain. For chemokine/ cytokine receptors, we found higher expression of TNF-α receptors, both TNFR2 and TNFR1, in the braid of sap-A^<-/-> mice. We also found a reduced expression of TNFR2 in the pregnant female sap-A^<-/-> mice. These results suggest the anti-inflammatory effect of pregnancy to the demyelinating brain lesions of sap-A^<-/-> mice. To further evaluate the effect of pregnancy and 17β-estradiol treatment, we are going to utilize DNA microarrays to elucidate global patterns of gene expression in the brain of sap-A^<-/-> mice. This approach would pickup the unknown gene other than the immune related genes and play define the protective mechanism of pregnancy in the demyelinating disease

我们已经产生了一个新的小鼠模型，迟发性，慢性形式的球状细胞脑白质病变（GLD，克拉伯病），通过引入突变（C106 F）鞘脂激活蛋白基因（saposin）的saposin A结构域。最有趣的是，我们发现在怀孕的saposin A缺陷（sap A^<1/1>）小鼠中有显著的临床和病理学改善。我们还发现，高水平的雌激素（17β-雌二醇）补充可以基本上复制sap-A^<-/->小鼠中的妊娠现象。基于这些证据，我们假设怀孕期间较高的雌性性激素如雌激素可以抑制小胶质细胞或巨噬细胞的活化，并防止它们在sap-A^<-/->小鼠的脱髓鞘脑损伤中产生有害分子。为了评估这一假设，我们分析了性别、妊娠或雌性激素补充对sap-A^<-/->小鼠脑中可变细胞因子和细胞因子受体的mRNA表达的可能影响。结果发现，sap-A_（1-x）小鼠脑组织中趋化因子和细胞因子表达显著上调</->，尤其是Rantes、MIP-1β、MIP-1α、MIP-2、MCP-1和TNF-α。在雌性或妊娠sap-A^<-/->小鼠脑中，Rantes、MIP-1 β、MIP-1α、MIP-2和MCP-1的这些上调被抑制。对于趋化因子/细胞因子受体，我们发现sap-A^<-/->小鼠的辫子中TNF-α受体（TNFR 2和TNFR 1）的表达更高。我们还发现在妊娠雌性sap-A^<-/->小鼠中TNFR 2的表达降低。这些结果表明妊娠对sap-A^<-/->小鼠的脱髓鞘脑损伤具有抗炎作用。为了进一步评估妊娠和17β-雌二醇治疗的效果，我们将利用DNA微阵列来阐明sap-A^<-/->小鼠脑中基因表达的总体模式。这种方法可以提取除免疫相关基因以外的未知基因，并对脱髓鞘疾病的妊娠保护机制进行研究