MOLECULAR MECHANISMS CONTRIBUTING TO GENDER DISPARITY IN MULTIPLE SCLEROSIS

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。 多发性硬化症(MS)影响着大约40万美国人，其中三分之二是女性。多发性硬化症的病因仍不清楚，但髓鞘蛋白可能是启动中枢神经系统炎症反应的自身抗原，性激素可能调节多发性硬化症的易感性。阐明这些激素影响小胶质细胞功能的机制以及了解重要的髓鞘特异性蛋白的调节对于了解多发性硬化症性别差异的基础至关重要。 该项目的目标是确定导致多发性硬化症性别偏见的分子机制，将通过观察iNOS的表达水平和调节来评估女性性激素对小胶质细胞功能调节的影响，iNOS是产生炎性分子的关键酶，负责该病特有的髓鞘随后的降解。将iNOS-荧光素酶构建物瞬时导入小胶质细胞以检测这一途径，近几个月来，实验室已经优化了用于这些转基因的有效系统。实验正在进行中，以评估iNOS的表达对添加到培养介质中的女性性类固醇的反应。 性激素对免疫反应的调节可能导致MS的性别差异，但潜在自身抗原在调节疾病易感性方面的性别特异性表达也可能起到作用。现有数据表明，编码成熟的中枢神经系统髓鞘中最丰富的蛋白质的PLP mRNA在小鼠睾丸的间质细胞中表达，而在雌性小鼠中没有外周表达。我们已经获得了证实PLP蛋白在睾丸组织中表达的蛋白质印迹数据。这种外周表达可能会在男性身上建立保护性耐受性。

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. Multiple sclerosis (MS) affects approximately 400,000 Americans, two-thirds of whom are female. The causes of MS remain elusive, but a myelin protein is likely to be the autoantigen responsible for initiating the inflammatory response in the CNS, and sex steroids may modulate susceptibility to MS. Elucidation of the mechanisms by which these hormones influence microglial function and an understanding of the regulation of important myelin-specific proteins will be crucial in understanding the basis of gender differences in MS. The goals of this project are to determine molecular mechanisms that result in a gender bias in MS. Effects of female sex steroids upon the regulation of microglia function will be assessed by looking at expression levels and regulation of iNOS, a key enzyme in the production of inflammatory molecules responsible for the subsequent degradation of myelin characteristic of the disease. Transient transfections of iNOS-luciferase constructs into microglial cells will be done to examine this pathway, and an efficient system for these transfections has been optimized in the lab in recent months. Experiments are underway to assess iNOS expression in response to female sex steroids added to culture media. Modulation of the immune response by sex steroids is likely to contribute to the gender disparity of MS, but gender-specific expression of potential autoantigens in mediating susceptibility to the disease may also contribute. Existing data demonstrate expression of Plp mRNA encoding the most abundant protein found in mature CNS myelin, previously thought to be expressed exclusively in the CNS, in Leydig cells of the testes of mice, with no peripheral expression in female counterparts. We have obtained Western blot data confirming expression of Plp protein in testicular tissue. It is possible this peripheral expression could establish protective tolerance in males.