Research Project 7: Estrogen Receptor-AhR Interactions in the CNS

类固醇！和非甾体类雌激素样化学物质（环境雌激素，EE），模拟或阻断 激素雌激素作用于雌激素受体（ER），二恶英类化学物质与 芳烃受体（AhR）广泛存在于环境中，是常见的污染物， 超级基金网站。雌激素受体介导的信号传导在神经发育过程中起着重要作用 以及维持成年和衰老大脑的神经可塑性和修复。虽然ER和 AhR/ARNT信号通路在外周组织中的多个点会聚，AhR的正常作用 中枢神经系统中的信号传导，以及ER-AhR相互作用的脑特异性机制和作用在很大程度上是 未知在这里，我们调查的假设，EE和二恶英是神经毒物，凭借他们的能力， 破坏中枢神经系统中的神经雌激素信号和雌激素反应基因。由此推论 一种假设是，对雌激素依赖的神经发育编程的不可逆化学作用 改变对激素雌激素和随后的EE和二恶英暴露的反应， 在成人和老年大脑中的神经可塑性和自我修复的组成部分。具体目标是： (1)确定ER和AhR信号通路对基因表达的单独和聚合作用 在发育编程过程中，以及在成年和衰老的大脑中;（2）确定相应的变化 雌激素反应神经基因和神经发育、神经可塑性和修复的细胞过程; (3)表征雌激素-二恶英对发育程序化替代物的作用和相互作用 CNS中的剪接决定;（4）鉴定介导雌激素的顺式元件和反式作用细胞因子 以及二恶英对神经元cyp 19 B基因启动子的作用和相互作用。

Steroida! and non-steroidal estrogen-like chemicals (environmental estrogens, EE) that mimic or block hormonal estrogen actions on estrogen receptors (ER), and dioxin-like chemicals that interact with arylhydrocarbon receptors (AhR), are widespread in the environment and common contaminants at Superfund sites. ER mediated signaling is known to have a critical role in neurodevelopmental programming and in the maintenance of neuroplasticity and repair in the adult and aging brain. Although ER and AhR/ARNT signaling pathways converge at multiple points in peripheral tissues, the normal role of AhR signaling in the CNS, and brain specific mechanisms and effects of ER-AhR interactions are largely unknown. Here we investigate the hypothesis that EE and dioxins are neurotoxicants, by virtue of their ability to disrupt neural estrogen signaling and estrogen responsive genes in the CNS. A corollary of this hypothesis is that irreversible chemical effects on estrogen dependent neurodevelopmentaf programming alter responses to hormonal estrogen and subsequent EE and dioxin exposures, and dysregulate estrogendependent components of neuroplasticity and self-repair in the adult and aging brain. Specific aims are to: (1) Determine separate and convergent actions of ER and AhR signaling pathways on gene expression during developmental programming, and in the adult and aging brain; (2) Determine corresponding changes in estrogen responsive neural genes and cellular processes of neurodevelopment, neuroplasticity and repair; (3) Characterize estrogen-dioxin actions and interactions on developmentally programmed alternative splicing decisions in the CNS; (4) Identify cis-elements and transacting cellular factors that mediate estrogen and dioxin actions and interactions on the neural cyp19B gene promoter.