Environmental Toxins and Uterine Gene Expression

环境毒素和子宫基因表达

• 批准号: 7891286
• 负责人: SANJOY K. DAS
• 金额: $ 33.41万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891286
• 关键词: Address; Animal Model; Biological; Biological Models; Biology; CCL4 gene; Cell Nucleolus; Cell Nucleus; Cell Proliferation; Cells; Chromatin; Coculture Techniques; Complement; Complex; DNA biosynthesis; Endoplasmic Reticulum; Epithelial Cell Proliferation; Estradiol; Estrogen Antagonists; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Event; Figs - dietary; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; Growth Factor; ICI 182780; In Vitro; Injection of therapeutic agent; Intervention; Investigation; Knockout Mice; Lactoferrin; Late Effects; Ligands; Mediating; Membrane; Modeling; Molecular; Molecular Genetics; Mus; Organ; Phase; Phosphorylation; Physiological; Play; Positioning Attribute; Protein Biosynthesis; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Stream; System; Testing; Tissues; Toxic Environmental Substances; Uterus; Water; Weight; Wild Type Mouse; Work; cell growth; in vitro Model; in vivo; inhibitor/antagonist; insight; kepone; knock-down; non-genomic; novel; promoter; public health relevance; response; uptake; xenoestrogen

DESCRIPTION (provided by applicant): Early- and late-phase estrogenic responses in the uterus have been recognized for more than 60 years, yet mechanisms involved in their regulation remain controversial. One concept is that an early events(s), occurring within the first 6 h, prepares the uterus for later (18-30 h) increase in DNA synthesis, cell proliferation and protein synthesis. An alternate view is that the late growth phase is a result of the continuous presence of a stimulus. Discussion of either concept usually makes the assumption that all of the responses are dependent upon ligand interaction with one of the two estrogen receptor isoforms (ER1 and ER2). However, increased gene expression following injection of estrogen or xenoestrogen, in mice lacking ER1, or in which all ER-activity has been suppressed by an estrogen-antagonist, ICI 182,780 (ICI), has shown this to be an oversimplification. In this regard, accumulating evidence suggests that estrogen regulates diverse but interdependent signaling pathways in uterine biology via ER- dependent and -independent manners. While our long standing hypothesis is that estrogenic certain early responses are ER-independent, late responses are ER1- dependent, and a cross-talk between the two phases is necessary for a full complement of estrogenic responses in the uterus. Our previous and preliminary observations suggest that among several such early genes, Bip and Sik-SP are induced by estradiol- 172 (E2) and kepone in the mouse uterus via ER-independent manner as a phase-I response. Moreover, we recently showed that Bip is critically necessary in mediating E2- or kepone-dependent estrogen signaling that involves ER1 functions. Our preliminary studies also indicated that E2 induces GPR30 and ERK1/2 phoshorylation without involving ER1. Furthermore, we observed that the administration of a selective inhibitor of ERK1/2 activation (SL327), 30 min prior to E2 injection abrogates early ER- independent genes, as well as uterine wet weights during the early and late responsive phases. In contrast, injection of the inhibitor 6 h after E2 injection did not alter late effects. Collectively, these results positioned us to study early and late estrogenic responses to determine molecular relationship between the phases. Our specific aims are to elucidate: 1. Early molecular signaling by E2 or kepone involving Sik-SP, Bip and GPR30 in the uterus. 2. Functional significance of Sik-SP and GPR30 in E2- or kepone- mediated late estrogenic responses in the uterus. Studies should yield new molecular insights involving Bip, Sik-SP and GPR30 during ER1-mediated estrogen signaling. Overall, the results will help us to define relationship and a molecular cross-talk between the two-phase estrogenic responses in the uterus. PUBLIC HEALTH RELEVANCE: Our specific aims are to elucidate: 1. Early molecular signaling by E2 or kepone involving Sik-SP, Bip and GPR30 in the uterus. 2. Functional significance of Sik-SP and GPR30 in E2 or kepone mediated late estrogenic responses in the uterus. Studies should yield new molecular insights involving Bip, Sik-SP and GPR30 regulation of ER1-mediated estrogen signaling. Overall, the results will help us to define the relationship and a molecular cross-talk between the two-phase estrogenic responses in the uterus.

描述（由申请人提供）：子宫中的早期和晚期雌激素反应已被认可已有60多年了，但是涉及调节的机制仍然存在争议。一个概念是，在前6小时内发生的早期事件会使子宫在DNA合成，细胞增殖和蛋白质合成中的稍后增加（18-30 h）。另一种观点是，晚期生长阶段是刺激持续存在的结果。对这两个概念的讨论通常会假设所有响应都取决于配体与两个雌激素受体同工型之一（ER1和ER2）的相互作用。然而，在缺乏ER1的小鼠中注射雌激素或异种雌激素后的基因表达增加，或者在其中所有ER活性被雌激素 - 抗逆邦剂ICI 182,780（ICI）抑制的小鼠表明这表明这是一个过度的简化。在这方面，积累的证据表明，雌激素通过依赖性和独立的方式调节子宫生物学中的多样化但相互依存的信号通路。尽管我们长期存在的假设是雌激素某些早期反应是与ER无关的，但较晚的反应是ER1的，并且在子宫中完全补充了雌激素反应的两个阶段之间的串扰是必要的。我们以前的初步观察结果表明，在几个这样的早期基因中，BIP和SIK-SP是由雌激素172（E2）（E2）和小鼠子宫中的kepone诱导的，它是通过ER非依赖性的方式作为相-I反应。此外，我们最近表明，在介导涉及ER1功能的E2或Kepone依赖性雌激素信号传导中，BIP至关重要。我们的初步研究还表明，E2诱导GPR30和ERK1/2哲学化，而无需ER1。此外，我们观察到，E2注射前30分钟的ERK1/2激活的选择性抑制剂（SL327）消除了早期ER-独立基因以及早期和晚期反应阶段的子宫湿重。相比之下，E2注射后6小时注射抑制剂不会改变后期作用。总的来说，这些结果使我们能够研究早期和晚期的雌激素反应，以确定相之间的分子关系。我们的具体目的是阐明：1。通过E2或Kepone涉及子宫中SIK-SP，BIP和GPR30的早期分子信号传导。 2。在子宫中E2或KEPONE介导的晚期雌激素反应中SIK-SP和GPR30的功能意义。研究应在ER1介导的雌激素信号传导过程中产生涉及BIP，SIK-SP和GPR30的新分子见解。总体而言，结果将有助于我们确定子宫中两相雌激素反应之间的关系和分子串扰。公共卫生相关性：我们的具体目的是阐明：1。涉及子宫中SIK-SP，BIP和GPR30的E2或KEPONE的早期分子信号传导。 2。在E2或KEPONE介导的子宫中的晚期雌激素反应中Sik-SP和GPR30的功能显着性。研究应产生涉及ER1介导的雌激素信号传导的BIP，SIK-SP和GPR30调控的新分子见解。总体而言，结果将有助于我们定义子宫中两相雌激素反应之间的关系和分子串扰。