Sex Chromosomes in Fetal Programming and Susceptibility to EAE

胎儿编程中的性染色体和 EAE 易感性

• 批准号: 7877725
• 负责人: CORY TEUSCHER
• 金额: $ 45.45万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877725
• 关键词: Accounting; Adoptive Transfer; Adult; Alleles; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Brothers; Cells; Central Nervous System Diseases; Clinical; Cohort Analysis; Conceptions; Consomic Strain; Control Locus; DNA; Disease; Disease susceptibility; Embryo; Embryo Transfer; Encephalomyelitis; Environment; Environmental Risk Factor; Etiology; Experimental Autoimmune Encephalomyelitis; Exposure to; Female; Fertilization in Vitro; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Immune; Immune response; Inflammatory; Inherited; Investigation; Knowledge; Life; Link; Mammals; Maps; Microchimerism; Modeling; Monozygotic Twinning; Monozygotic twins; Multiple Sclerosis; Mus; Neonatal; Neuraxis; Organ; Parents; Pattern; Phenotype; Play; Predisposition; Pregnancy; Reporting; Resistance; Risk; Role; Sampling; Sex Chromosomes; Siblings; Source; Testing; Testis; Testosterone; Transgenic Model; Twin Multiple Birth; Woman; Y Chromosome; consomic; fetal programming; gene environment interaction; in utero; male; novel; public health relevance; sex; sexual dimorphism; sperm cell; young adult

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.

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) 模型是实验性过敏性脑脊髓炎 (EAE)。遗传学、环境以及基因与环境之间的相互作用会导致 MS 和 EAE 的疾病易感性和进展。我们最近证明，Y 染色体上的一个基因座 Yeae 会影响雄性和雌性小鼠对 EAE 的易感性。因为只有雄性后代继承 Y 染色体，所以可以认为 Yeae 的影响仅限于雄性；然而，我们证明 Yeae 也会影响成年女性的 EAE。 Yeae 如何实现雌性小鼠 EAE 的组织男性化是我们知识中的一个主要空白。在本申请中，我们建议测试以下假设：雌性后代与雄性细胞的妊娠微嵌合是 Yeae 导致雌性小鼠中 EAE 组织男性化的机制。具体来说，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产生的全雌性、全雄性和混合性别操纵的窝中的 EAE。这将直接确定女性的 Yeae 效应是否是由于暴露于子宫内的兄弟而引起的。此外，还将对转录组和免疫反应（目标 2）进行表征。最后，在目标 3 中，我们将检验 Yeae 可能是 Sry 的假设，以及 Yeae 和常染色体基因座之间的相互作用控制女性 EAE 的组织男性化。 公共健康相关性：这些研究的结果与最近发现的多发性硬化症同卵双胞胎中微嵌合现象增加直接相关，并且有可能显着增强我们对妊娠环境在“胎儿编程”对成人发病的人工智能疾病（如多发性硬化症）的易感性和抵抗力中所起的作用的理解。