| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2003: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2002: ¥9,100,000 (Direct Cost: ¥9,100,000)
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| Research Abstract |
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
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