Developmental Programming of Endometriosis Genes

描述（由申请人提供）：虽然子宫内膜异位症的病因可能是多因素的，但本项目的长期目标是了解最近发现的由发育性雌激素编程引起的子宫内膜异位症的成分。将人类发育性DES暴露与我们在小鼠中的初步数据联系起来的数据导致了这样的假设：发育性异雌激素暴露通过改变DNA甲基化来控制胎儿，并在成年期加剧子宫内膜异位症。提出了三个具体目标。具体目标发育过程中暴露于双酚A、染料木素和乙炔雌二醇是否会加剧成年期子宫内膜异位症？我们已经证明，在手术诱导的子宫内膜异位症小鼠模型中，发育性暴露于DES会增加子宫内膜异位症病变中的细胞增殖，并导致相对于对照小鼠更大的病变。在发育暴露于双酚A、染料木素、炔雌醇或DES后，我们将通过手术诱导成年小鼠子宫内膜异位症。4周后测量病变重量、细胞增殖、细胞凋亡和血管新生。具体目标2。发育性异种雌激素暴露会影响子宫内膜异位症病变的基因表达吗？我们已经表明，发育暴露于DES改变子宫内膜异位症病变中细胞外基质和粘附分子的表达。在发育性异雌激素暴露和成年期子宫内膜异位症手术诱导后，我们将使用从子宫内膜异位症病变中分离的RNA来探测Illumina小鼠8微阵列。具体目标3。发育性雌激素暴露是否会改变子宫内膜异位症病变中基因的DNA甲基化？人类子宫内膜异位症组织中的许多基因最近被发现与DNA甲基化改变有关。在一项初步研究中，我们已经表明，在发育期间暴露于DES或乙炔雌二醇会改变异位子宫内膜的DNA甲基化谱。我们将使用小鼠甲基化CpG岛扩增（MCA）作为筛选小鼠CpG岛DNA甲基化改变的全球方法。这个项目有可能导致使用改变DNA甲基化的药物治疗子宫内膜异位症的新疗法。在更广泛的背景下，该项目可能会确定候选基因和它们的蛋白质，这些基因和蛋白质可以用作新疗法的靶标。此外，雌激素暴露与成年期子宫内膜异位症恶化之间的因果关系是通过减少暴露于这些环境化学物质进行干预的主要目标。公共卫生相关性：胎儿暴露于雌激素环境化学物质与成年后子宫内膜异位症之间的因果关系是通过减少暴露于这些环境化学物质并可能降低子宫内膜异位症严重程度进行干预的主要目标。此外，该项目有可能导致使用改变DNA甲基化的药物治疗子宫内膜异位症的新疗法。在更广泛的背景下，该项目可能会确定候选基因及其蛋白，这些基因和蛋白可以作为治疗和治愈子宫内膜异位症的新疗法的靶点。

DESCRIPTION (provided by applicant): While the etiology of endometriosis is likely multifactorial, the long-range goal of this project is to understand a recently identified component to endometriosis due to developmental estrogen programming. The data linking developmental DES exposure in humans and our preliminary data in mice have led to the hypothesis: Developmental xenoestrogen exposure programs the fetus by altered DNA methylation and exacerbates endometriosis in adulthood. Three specific aims are proposed. Specific Aim 1. Does developmental exposure to bisphenol A, genistein and ethinyl estradiol at current human exposure levels exacerbate endometriosis in adulthood. We have shown that developmental DES exposure increases cell proliferation in endometriotic lesions in a mouse model of surgically induced endometriosis and results in larger lesions relative to control mice. After developmental exposure to bisphenol A, genistein, ethinyl estradiol or DES, we will surgically induce endometriosis in adult mice. Four weeks later, we will measure lesion weight, cell proliferation, apoptosis and angiogenesis. Specific Aim 2. Does developmental xenoestrogen exposure program gene expression in endometriotic lesions? We have shown that developmental DES exposure alters the expression of extracellular matrix and adhesion molecules in endometriotic lesions. After developmental xenoestrogen exposure and surgical induction of endometriosis in adulthood, we will use RNA isolated from endometriotic lesions to probe Illumina mouseref 8 microarrays. Specific Aim 3. Does developmental xenoestrogen exposure alter DNA methylation of genes in endometriotic lesions. Many genes in human endometriotic tissue have recently been identified with altered DNA methylation. In a preliminary study, we have shown that exposure to DES or ethinyl estradiol during development alters the DNA methylation profile in eutopic endometrium. We will use mouse methylated CpG island amplification (MCA) as a global approach to screen mouse CpG islands for altered DNA methylation. This project has the potential to lead to new therapeutics for treatment of endometriosis with drugs that alter DNA methylation. In a broader context, this project is likely to identify candidate genes and their proteins that can be used as targets for novel therapeutics. Further, a causal relationship between xenoestrogen exposure and exacerbation of endometriosis in adulthood represents a prime target for intervention by reducing exposure to these environmental chemicals. PUBLIC HEALTH RELEVANCE: A causal relationship between fetal exposure to estrogenic environmental chemicals and endometriosis in adulthood represents a prime target for intervention by reducing exposure to these environmental chemicals and to perhaps decrease the severity of endometriosis. Further, this project has the potential to lead to new therapeutics for treatment of endometriosis with drugs that alter DNA methylation. In a broader context, this project is likely to identify candidate genes and their proteins that can be used as targets for novel therapeutics in the treatment and possible cure of endometriosis.