IMMUNOPATHOLOGIC ALTERATIONS IN RHESUS MACAQUES WITH GLOBOID CELL LEUKODYSTROPHY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 类球形细胞白质营养不良症，又称Krabbe病，是由于半乳糖脑苷酶(GALC)活性缺乏引起的一种严重的中枢和外周神经系统疾病。我们先前已经确定，感染Krabbe病的恒河猴在受影响的白质中iNOS、TNF-α和IL-1的表达水平显著增加，与球状细胞、激活的小胶质细胞和星形胶质细胞共存。细胞因子mRNA水平显示，受影响的猕猴脑内CCL2基因表达显著增加。CCL2阳性细胞分布于受累脑白质内，与GFAP细胞和星形胶质细胞共存。我们目前正在使用BioPlex分析对疾病进展的不同阶段的细胞因子变化进行完整的分析。Krabbe的脑白质样本正被直接与年龄和性别匹配的对照大脑样本进行比较，这些样本来自未受影响的动物。希望这一分析将提供对炎症过程在疾病进展中所起作用的洞察，并确定潜在的治疗干预靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Globoid cell leukodystrophy, or Krabbe's disease, is a severe disorder of the central and peripheral nervous system caused by the absence of galactocerebrosidase (GALC) activity. We have previously determined that rhesus macaques affected with Krabbe's disease demonstrated marked increases in the levels of expression of iNOS, TNF-alpha, and IL-1 in the affected white matter, colocalizing with globoid cells, activated microglia, and astrocytes. Cytokine mRNA levels revealed markedly increased gene expression of CCL2 in the brain of affected macaques. CCL2-expressing cells were detected throughout the affected white matter, colocalizing with GFAP cells and astrocytes. We are presently performing as complete analysis of cytokine alterations using a Bioplex analysis at various stages of disease progression. Krabbe brain white matter samples are being directly compared to age and sex matched control brain samples form unaffected animals. It is hoped that this analysis will provide insight in to the role that the inflammatory process plays in the disease progression and to identify potential targets for therapeutic intervention.