MECHANISM OF ACTION OF STEROID HORMONE

描述：研究者研究的长期目标是 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，将阐明 临床上重要的激素效应。 目前的重点是 糖皮质激素对诱导型前列腺素G/H合酶的抑制， 环氧合酶-2（考克斯-2），这似乎是许多人中的关键步骤。 不同的糖皮质激素作用。 考克斯-2是一个即刻早期基因， 由刺激生长的试剂（生长因子，细胞因子， 有丝分裂原和致癌基因），并由创伤大量诱导。 安理会加大 表达在许多病理学中起关键作用，包括：急性 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。 的重点 建议是检查E4 BP 4作为介导剂的假设， 将研究糖皮质激素对这些和/或其他基因的作用 iNOS启动子的调节，其响应于E4 BP 4，并且在 本课程开发了一个稳定整合的表达系统，以研究E4 BP 4的作用 对细胞基因的影响。 特异性目标2将分析考克斯-2启动子， 利用根据具体目标1开发的系统研究E4 BP 4的作用 内源性考克斯-2基因。 专属性的确认 影响将通过突变，竞争抑制， E4 BP 4的特异性拮抗剂的表达。 在具体目标3中，对单个细胞mRNA和 将进行蛋白质测定，以进一步确定 一方面，个体基因对糖皮质激素的反应，另一方面， 另一个，通过在回应中寻求身份，以及一个人的能力， E4 BP 4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