Sex Chromosomes in Fetal Programming and Susceptibility to EAE

描述(申请人提供)：多发性硬化症(MS)是中枢神经系统的主要炎症性疾病。MS的主要自身免疫(AI)模型为实验性变态反应性脑脊髓炎(EAE)。遗传、环境和基因与环境的相互作用有助于MS和EAE的疾病易感性和进展。我们最近证实，Y染色体上的一个基因座Yae影响雄性和雌性小鼠对EAE的易感性。因为只有男性后代才会遗传Y染色体，所以可以假设YEA的作用仅限于男性；然而，我们证明了YEA也影响成年女性的EAE。YEA如何在雌性小鼠体内实现EAE的组织化是我们认识上的一个主要空白。在这一应用中，我们建议检验这样一种假设，即雌性后代与雄性细胞的妊娠微嵌合体是YEA导致雌性小鼠EAE组织男性化的机制。具体地说，在目标1中，我们将研究通过体外受精和将性别选择的胚胎移植到代孕雌性所产生的全雌性、全雄性和混合性操纵产仔的EAE。这将直接确定女性的YEA效应是否是由于在子宫中接触她们的兄弟。此外，还将描述转录本和免疫反应(目标2)。最后，在目标3中，我们将检验YEA可能是Sry的假设，以及Yae与常染色体基因座之间的交互作用控制着EAE在女性中的组织男性化。 公共卫生相关性：这些研究的结果与最近发现的符合MS的MZ双胞胎微嵌合体增加直接相关，并有可能显著增强我们对妊娠环境在对MS等成人发病的AI疾病的易感性和抵抗力方面所起的作用的理解。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the major inflammatory disease of the central nervous system. The principal autoimmune (AI) model of MS is experimental allergic encephalomyelitis (EAE). Genetics, environment and gene-by-environment interactions contribute to disease susceptibility and progression in both MS and EAE. We recently demonstrated that Yeae, a locus on the Y chromosome, influences susceptibility to EAE in both male and female mice. Because only male progeny inherit the Y chromosome, it might be assumed that the effects of Yeae would be restricted to males; however, we proved that Yeae also influences EAE in adult females. It is a major gap in our knowledge how the organizational masculinization of EAE in female mice by Yeae is achieved. In this application we propose to test the hypothesis that gestational microchimerism of female progeny with male cells is the mechanism whereby Yeae leads to the organizational masculinization of EAE in female mice. Specifically, in Aim 1 we will study EAE in all-female, all-male and mixed sex manipulated litters generated by in vitro fertilization and transfer of sex-selected embryos to surrogate females. This will directly ascertain whether or not the Yeae effect in females is due to exposure to their brothers in utero. Additionally, the transcriptomes and immune responses (Aim 2) will be characterized. Lastly, in Aim 3 we will test the hypothesis that Yeae may be Sry and that interaction between Yeae and autosomal loci control the organizational masculinization of EAE in females. PUBLIC HEALTH RELEVANCE: The result of these studies are directly relevant to the recent finding of increased microchimerism in MZ twins concordant for MS and have the potential to significantly enhance our understanding of the role that the gestational environment plays in `fetal programming' of susceptibility and resistance to adult onset AI disease such as MS.