MECHANISM OF ACTION OF STEROID HORMONE

描述：研究人员的长期目标是 了解参与启动的分子和代谢事件 糖皮质激素的作用，使用模型系统将揭示 临床上重要的荷尔蒙效应。目前的焦点是 糖皮质激素对诱导型前列腺素G/H合酶的抑制作用 环氧合酶-2(COX-2)，这似乎是许多 不同的糖皮质激素作用。COX-2是一种即刻早期基因， 由刺激生长的物质(生长因子、细胞因子、 有丝分裂原和癌基因)，并由创伤大量诱导。它增加了 表达在许多病理过程中起着关键作用，包括：急性 以及慢性炎症性疾病、阿尔茨海默病、心血管疾病 疾病，以及一些肺癌、结肠癌和皮肤癌。这件事的重点是 建议检验E4BP4作为调节因子的假设 糖皮质激素对这些和/或其他特定基因的作用将进行研究 反应E4BP4的iNOS启动子的调节，以及在 课程开发稳定整合的表达系统研究E4BP4的作用 在细胞基因上。《特定目标2》将分析COX-2启动子和 利用在特定目标1下开发的系统来研究E4BP4的作用 内源性COX-2基因。确认这一事件的特殊性 效果将通过突变、竞争抑制和 E4BP4特异性拮抗剂的表达 在具体目标3中，对单个细胞mRNAs和 将进行蛋白质测试，以进一步确定 一方面，个体基因对糖皮质激素的反应，以及E4BP4对糖皮质激素的影响 另一种是通过在回应中寻找身份，以及通过一个 E4BP4拮抗剂选择性阻断单个基因的反应

DESCRIPTION: The long-term goal of the investigator's research is to understan the molecular and metabolic events involved in the initiation of glucocorticoi hormone actions, using model systems that will shed light on clinically important hormone effects. The current focus is on the glucocorticoid inhibition of the inducible prostaglandin G/H synthase, cyclooxygenase-2 (Cox-2), which appears to be the critical step in many diverse glucocorticoid actions. Cox-2 is an immediate-early gene, rapidly induced by agents that stimulate growth (growth factors, cytokines, mitogens, and oncogenes), and massively induced by trauma. Its increased expression plays a critical role in many pathologies that include: acute and chronic inflammatory diseases, Alzheimer's disease, cardiovascular disease, and some cancers of the lung, colon and skin. The focus of this proposal is to examine the hypothesis that E4BP4 serves as mediator of glucocorticoid actions on these and/or other genes Specific Aim 1 will study the regulation of the iNOS promoter, which responds to E4BP4, and in the course develop a stably integrated expression system to study E4BP4 actions on the cellular genes. Specific Aim 2 will analyze the Cox-2 promoter and utilize the systems developed under Specific Aim 1 to study actions of E4BP4 on the endogenous Cox-2 gene. Confirmation of the specificity of the effects will be achieved through mutations, competitive inhibitions, an expression of a specific antagonist to E4BP4. In Specific Aim 3, a more global analysis of individual cellular mRNAs and proteins will be performed to further establish the specificity of individual gene responses to glucocorticoids on the one hand, and E4BP4 on the other, by seeking identities in the responses, and by the ability of an E4BP4 antagonist to selectively block the responses of individual genes