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

斯特罗伊达！和非类固醇雌激素类化学物质(环境雌激素，EE)，模拟或阻断 激素对雌激素受体(ER)的作用，以及与之相互作用的二恶英类化学物质 芳烃受体(AhR)广泛存在于环境和环境中的常见污染物 超级基金网站。已知内质网介导的信号在神经发育编程中起着关键作用 以及在成人和老化的大脑中维持神经可塑性和修复。虽然ER和 AHR/Arnt信号通路在外周组织中多点汇聚，AhR的正常作用 中枢神经系统中的信号，以及ER-AhR相互作用的大脑特定机制和影响 未知。在这里，我们调查了EE和二恶英是神经毒物的假设，这是由于它们的能力 干扰中枢神经雌激素信号和雌激素反应基因。这是一个必然结果 假说是雌激素依赖神经发育的不可逆转的化学效应 改变对激素雌激素以及随后的EE和二恶英暴露的反应，并失调雌激素依赖性 成人脑和老年脑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分离和融合作用 在发育规划过程中，以及在成人和衰老的大脑中；(2)确定相应的变化 在雌激素反应神经基因和细胞过程中的神经发育、神经可塑性和修复； (3)研究雌激素和二恶英在发育程序性替代物中的作用和相互作用 中枢神经系统中的剪接决定；(4)识别调节雌激素的顺式元件和交易细胞因子 以及二恶英对神经型cyp19B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.