MECHANISM OF ACTION OF STEROID HORMONES

长期目标是了解分子和 参与启动和实施的代谢事件 肾上腺糖皮质激素的生物学效应。 我们在实现这一目标方面取得了进展， 少数（6-11）非常快速的蛋白质和mRNA诱导， 似乎启动了每个正常人的激素效应 靶组织;胸腺、脂肪、肝脏和成纤维细胞。 之一 这些，葡萄糖皮质激素，是特别感兴趣的，因为最快速的 在所有靶细胞中诱导。 另一方面，蛋白质1 N可能是 葡萄糖转运的生理抑制剂和/或 脂皮质素家族 我们继续调查的部分目的是提供 更多关于这些调解人的详细信息， 靶细胞 对诱导机制的研究将整理出 主要和次要响应，并收集更多信息 关于亚细胞位置，DNA结合，和结构 与其他分子的关系。 我们将调查 各种糖皮质激素个体诱导的特异性 以可能的子分类为目的。 我们将进一步 通过观察调解员的行动来调查职能 自身和抗体在地下系统中。 其他工作旨在开发寡核苷酸， 抗体探针 然后，从葡萄糖皮质激素开始， 进行分子克隆。 除了结构 这些蛋白质及其基因的信息， 允许最终使用表达载体用于进一步的 探索它们在培养细胞中的功能。 临床相关性。 治疗的好处， 免疫抑制和抗炎作用 糖皮质激素提供在慢性疾病状态，器官 移植和癌症化疗都被生命所抵消， 骨吸收和结缔组织的威胁性副作用 浪费 似乎个体的中介者 糖皮质激素作用本身或相关治疗剂 通过基因工程获得的最终将提供给 临床医生用于产生糖皮质激素的期望作用 没有这些不幸的副作用。 这些研究还将 提供有关生物调节机制的基本信息 所以基本信息最终可能 与艾滋病研究有关。

The long-term objectives are to understand the molecular and metabolic events involved in the initiation and implementation of each of the biological effects of adrenal glucocorticoid hormones. We have made progress towards this goal by the discovery of a few (6-11) very rapid inductions of proteins and mRNAs that appear to initiate the hormone effects in each of the normal target tissues; thymus, fat, liver and fibroblastic cells. One of these, glucocortin, is of special interest as the most rapid induction in all target cells. Another, protein 1N may be the physiological inhibitor of glucose transport and/or a member of the lipocortin family. Portions of our continuing investigations are aimed providing more detailed information about these mediators in the different target cells. Studies on induction mechanisms will sort out primary and secondary responses and gather further information about subcellular locations, DNA binding, and structural relationships with other molecules. We will investigate the specificity of individual inductions for a variety of glucocorticoids with aim of possible sub-classifications. We will further investigate functions by observing the actions of the mediators themselves and antibodies to them in subcellar systems. Other work is aimed at the development of oligonucleotide and antibody probes. Then, starting with glucocortin we will undertake molecular cloning. In addition to the structural information gained about these proteins and their genes this will allow the eventual use of expression vectors for the further exploration of their functions in cultured cells. Clinical relevance. The therapeutic benefits that immunosuppressive and anti-inflammatory effects of glucocorticoids offer in chronic disease states, organ transplantation, and cancer chemotherapy are offset by the life- threatening side effects of bone resorption and connective tissue wasting. It seems likely that mediators of the individual glucocorticoid actions themselves or related therapeutic agents derived by genetic engineering will eventually be available to the clinician for the production of desirable actions of glucocorticoids without these unfortunate side effects. These studies will also provide fundamental information about bioregulatory mechanisms in thymus cells; so the fundamental information may eventually have relevance to research on AIDS.