GLUCOCORTICOIDS IN EPIDERMIS: MECHANISMS OF ACTION

描述：（改编自申请人的摘要）-本提案的重点是 GC是一种重要的生理和药理调节剂， 表皮生长、分化和体内平衡，并广泛用于 治疗急性和慢性皮肤病。GC抑制伤口愈合 和免疫反应，并且是生长抑制剂。然而，精确 GC执行其功能的分子机制在很大程度上是未知的。在 为了开发更有效的治疗皮肤疾病， 副作用，这是研究者的长期目标，她希望 了解GC在皮肤中的作用为此，她目前的目标是 已经描述了皮质类固醇调节的分子机制， 表皮，特别是GCs调节角蛋白基因的机制 表情角蛋白是上皮发育的表型标志物， 分化和致病状态。首席调查员和她 他的同事们得出的数据表明，某些激素和维生素，如 作为GC和视黄酸，通过以下途径直接调节角蛋白基因表达： 它们的核受体首席研究员发现GC受体 使用一种新的机制来调节角蛋白基因的表达。在这 建议，主要研究者希望定义和描述 正是这种新颖的机制。在提案中，首席研究员 计划描述GC受体和 角蛋白基因上受体的识别位点。其次，她计划 定义参与这些的GC受体的特定区域， 受体-基因相互作用第三，她希望界定共同监管机构（其他 相互作用蛋白）参与GC受体和 角蛋白基因首席研究员认为计划中的实验 将产生新的见解和知识， GC受体是一种重要的转录因子， 角蛋白基因表达，特别是其在皮肤中的作用。这个新 知识可以导致更好的治疗患者的发展， 皮肤疾病，更有效的治疗， 的影响，并针对性地解决疾病的原因，而不仅仅是 减轻症状。

DESCRIPTION: (Adapted from the applicant's abstract) - This proposal focuses on GCs, hormones that are important physiologic and pharmacologic regulators of epidermal growth, differentiation, and homeostasis, and are extensively used in treatment of both acute and chronic skin diseases. GCs inhibit wound healing and immune responses and are growth inhibitory agents. However, the precise molecular mechanism by which GCs perform their function is largely unknown. In order to develop more effective treatment of cutaneous disorders with minimal side effects, which is the investigator's long-term goal, she wishes to understand how GCs operate in the skin. Towards this end, her current goal has been to characterize the molecular mechanisms of corticosteroid regulation in epidermis, specifically on the mechanisms by which GCs regulate keratin gene expression. Keratins are phenotypic markers of epithelial development, differentiation, and pathogenic states. The principal investigator and her colleagues have generated data to show that certain hormones and vitamins, such as GCs and retinoic acid, directly regulate keratin gene expression through their nuclear receptors. The principal investigator found that the GC receptor uses a novel mechanism for regulation of keratin gene expression. In this proposal, the principal investigator wishes to define and characterize precisely this novel mechanism. In the proposal, the principal investigator plans to characterize the molecular interactions between the GC receptor and the recognition sites for the receptor on keratin genes. Second, she plans to define the particular regions of the GC receptor involved in these receptor-gene interactions. Third, she wishes to define co-regulators (other interactive proteins) involved in the interaction between the GC receptor and keratin genes. The principal investigator believes that the experiments planned will generate new insights and knowledge to provide an understanding of the mechanism of action of the GC receptor, an important transcription factor for keratin gene expression, and, in particular, its effects in skin. This new knowledge could lead to the development of better treatments of patients with cutaneous disorders, treatments that are more effective, have less side effects, and are targeted to address the causes of the disease and not just alleviate the symptoms.