Sex Chromosomes in Fetal Programming and Susceptibility to EAE

描述（由申请人提供）：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）模型是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。我们最近证明了Y染色体上的一个位点Yeae影响雄性和雌性小鼠对EAE的易感性。因为只有男性后代继承Y染色体，它可能被认为是Yeae的影响将仅限于男性，然而，我们证明了Yeae也影响成年女性的EAE。这是一个主要的差距，我们的知识如何在雌性小鼠的EAE的组织雄性化的Yeae实现。在这个应用程序中，我们提出了测试的假设，妊娠微嵌合体的雌性后代与雄性细胞的机制，Yeae导致组织雄性化的EAE在雌性小鼠。具体而言，在目标1中，我们将研究EAE在所有女性，所有男性和混合性别操纵的窝产生的体外受精和性别选择的胚胎移植到代孕女性。这将直接确定雌性中的Yeae效应是否是由于暴露于子宫内的兄弟。此外，将对转录组和免疫应答（目的2）进行表征。最后，在目标3中，我们将测试的假设，Yeae可能是Sry和Yeae和常染色体基因座之间的相互作用控制的组织男性化的EAE在女性。 公共卫生相关性：这些研究的结果与最近发现的与MS一致的MZ双胞胎中微嵌合体增加直接相关，并且有可能显著增强我们对妊娠环境在成人发病AI疾病（如MS）的易感性和抵抗性的“胎儿编程”中所起作用的理解。

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.