UTERINE DISRUPTION: DNA METHYLATION & EPITHELIA-STROMA

子宫破坏：DNA 甲基化

• 批准号: 6740254
• 负责人: WILLIAM J HENDRY
• 金额: $ 14.29万
• 依托单位: WICHITA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-18 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740254
• 关键词: DNA methylation; cell cell interaction; cell proliferation; developmental disease /disorder; developmental genetics; diethylstilbestrol; embryo /fetus drug adverse effect; endocrine disorder; estrogens; gene expression; genetic screening; hamsters; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; mesenchyme; plasmids; reproductive development; uterus

DESCRIPTION (provided by applicant): The long-term objectives are to: 1) determine the basic mechanisms whereby estrogen regulates normal patterns of cell proliferation and tissue morphogenesis in reproductive tract organs; and 2) identify causal links between disruption of normal estrogen responses and alterations in specific cellular events and molecular factors. The PI has determined that neonatal treatment with the established endocrine-disrupting agent, diethylstilbestrol (DES), directly and permanently alters the developing hamster uterus (initiation phase) so that the adult hamster uterus responds abnormally to stimulation (promotion phase) with the natural estrogen, estradiol. A primary working hypothesis (WH) that is consistent with that phenomenon and is responsive to the fetal/developmental focus of the Program Announcement is: 1' WH-Alterations in DNA methylation during early development are part of the mechanism by which neonatal DES exposure permanently disrupts uterine morphogenesis and estrogen responsiveness. A secondary working hypothesis that incorporates new information about the mechanisms that regulate development and function of estrogen-responsive organs is: 2' WH-The involvement of epithelial-stromal (mesenchymal) interactions in uterine development and function makes it likely that the extent or pattern of neonatal DES-altered methylation will differ between the two tissue compartments. The following set of Specific Aims (SA) represents an innovative but feasible strategy to test those linked hypotheses. SA#1-Screen for evidence of tissue specific differences in DNA methylation that occur during the initiation phase of neonatal DES-induced uterine disruption. SA#2-Determine if products from the screen are linked either to known genes or to previously unidentified (novel) genes that are differentially expressed in the control vs. neonatally DES-disrupted hamster uterus. SA#3-At the tissue-specific level, evaluate the relationship between neonatal DES-induced alterations in DNA methylation and subsequent changes in gene expression within the hamster uterus. A more complete understanding of such intercellular and genomic dynamics will help generate new strategies to: 1) better evaluate the stage/grade of disease progression, and 2) better choose and deliver therapeutic agents. It should also yield important new insight into the topic of 'endocrine disruption'.

描述（由申请人提供）：长期目标是：1）确定雌激素调节生殖道器官中细胞增殖和组织形态发生的正常模式的基本机制； 2) 确定正常雌激素反应的破坏与特定细胞事件和分子因素的改变之间的因果关系。 PI 已确定，使用已确定的内分泌干扰剂己烯雌酚 (DES) 进行新生儿治疗会直接且永久地改变发育中的仓鼠子宫（起始阶段），从而使成年仓鼠子宫对天然雌激素的刺激（促进阶段）做出异常反应，雌二醇。与该现象一致并响应计划公告的胎儿/发育重点的主要工作假设 (WH) 是： 1' WH-早期发育过程中 DNA 甲基化的改变是新生儿 DES 永久暴露机制的一部分破坏子宫形态发生和雌激素反应性。包含有关调节雌激素反应器官发育和功能的机制的新信息的次要工作假设是：2'WH-子宫发育和功能中上皮-间质（间质）相互作用的参与使得子宫发育和功能的程度或模式很可能是这样的：新生儿 DES 改变的甲基化在两个组织区室之间会有所不同。以下一组具体目标 (SA) 代表了一种创新但可行的策略来测试这些相关假设。 SA#1-筛选在新生儿 DES 诱导的子宫破坏起始阶段发生的 DNA 甲基化组织特异性差异的证据。 SA#2-确定筛选产物是否与已知基因或先前未识别的（新）基因相关，这些基因在对照与新生 DES 破坏的仓鼠子宫中差异表达。 SA#3-在组织特异性水平上，评估新生儿 DES 诱导的 DNA 甲基化改变与仓鼠子宫内基因表达的后续变化之间的关系。对这种细胞间和基因组动力学的更全面的了解将有助于产生新的策略：1）更好地评估疾病进展的阶段/等级，2）更好地选择和提供治疗药物。它还应该对“内分泌干扰”主题产生重要的新见解。