Actions of Estrogen & Environmental Estrogens on Neurons

雌激素的作用

• 批准号: 6748500
• 负责人: SCOTT M BELCHER
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748500
• 关键词: biological signal transduction; cerebellum; complementary DNA; developmental neurobiology; environmental exposure; estradiol; estrogen receptors; estrogens; gene expression; hormone regulation /control mechanism; laboratory rat; microarray technology; mitogen activated protein kinase; neurons; neurotoxicology; polymerase chain reaction; western blottings

DESCRIPTION (provided by applicant): The broad long-term goal of the proposed research is to understand the functions of 17beta-estradiol (estrogen; E2) and estrogen receptors (ERs) in the developing nervous system and to determine to what extent environmental estrogens influence these functions. E2 influences the development and function of many regions of the brain in both males and females. Thus, it is possible that other estrogenic compounds can impact development of the brain. Environmental estrogens, also known as "endocrine disrupters," are a diverse group of compounds that can mimic or antagonize the normal actions of E2. The extent to which environmental estrogens impact the developing nervous system is unclear. Proposed experiments employing primary cultures of neonatal rat cerebellar neurons and the developing cerebellum as models will address the following Specific Aims-Specific Aim 1: Determine whether E2 modulates cellular signaling in developing cerebellar neurons through rapid, non-genomic actions on MAPK signal transduction; Specific Aim 2: Determine the networks of estrogen responsive genes whose expression is modulated by E2 in cerebellar neurons; Specific Aim 3: Determine to what degree representative environmental estrogens mimic or inhibit the effects of E2 in developing cerebellar neurons. Specific Aims 1 & 2 test the hypothesis that E2 normally functions in developing neurons by rapidly modulating the activity of MAPK signaling, and also through genomic ER-mediated mechanisms which together, modify expression of discrete networks of gene products. Specific Aim 3 will test the hypothesis that environmental estrogens influence developing neurons by modifying both MAPK signaling and genomic ER-mediated mechanisms, which results in altered networks of expressed genes. All three Specific Aims will be addressed through experiments using activation-state specific antisera to determine E2-mediated signaling pathways and by cDNA array and RT -PCR analysis of E2-responsive gene expression. From these results a neuronal "E2-signature cDNA array" will be developed and used in Aim 3 to determine how environmental estrogens influence E2-responsive gene expression in these developing neurons.

描述（由申请人提供）：拟议研究的广泛长期目标是了解17 β-雌二醇（雌激素; E2）和雌激素受体（ER）在发育神经系统中的功能，并确定环境雌激素对这些功能的影响程度。E2影响男性和女性大脑许多区域的发育和功能。因此，其他雌激素化合物可能会影响大脑的发育。环境雌激素，也被称为“内分泌干扰物”，是一组不同的化合物，可以模拟或拮抗E2的正常作用。环境雌激素对发育中的神经系统的影响程度尚不清楚。采用新生大鼠小脑神经元原代培养物和发育中的小脑作为模型的实验将解决以下特定目的-特定目的1：确定E2是否通过对MAPK信号转导的快速、非基因组作用来调节发育中的小脑神经元中的细胞信号传导;特定目的2：确定小脑神经元中其表达受E2调节的雌激素应答基因的网络;具体目标3：确定在何种程度上代表性的环境雌激素模拟或抑制E2在小脑神经元发育中的作用。具体目标1和2测试E2通过快速调节MAPK信号传导的活性以及通过基因组ER介导的机制在发育中的神经元中正常起作用的假设，所述机制一起修饰基因产物的离散网络的表达。具体目标3将测试环境雌激素通过修饰MAPK信号传导和基因组ER介导的机制影响发育中的神经元的假设，这导致表达基因的网络改变。将通过使用激活状态特异性抗血清的实验来确定E2介导的信号传导途径，并通过cDNA阵列和E2响应基因表达的RT-PCR分析来解决所有三个特定目的。从这些结果的神经元“E2-签名cDNA阵列”将开发和使用的目的3，以确定如何环境雌激素影响E2-响应基因表达在这些发展中的神经元。