GLUCOCORTICOIDS IN EPIDERMIS: MECHANISMS OF ACTION

描述：(改编自申请人的摘要)-本提案侧重于 GCS是一种重要的生理和药物调节激素 表皮生长、分化和动态平衡，广泛用于 治疗急慢性皮肤病。GCS抑制伤口愈合 和免疫反应，是生长抑制剂。然而，准确的 GC执行其功能的分子机制在很大程度上是未知的。在……里面 为了开发更有效的治疗皮肤病的最小剂量 副作用，这是研究人员的长期目标，她希望 了解GC是如何在皮肤中运作的。为此，她目前的目标是 一直在研究皮质类固醇激素调节的分子机制。 表皮，特别是GCs调控角蛋白基因的机制 表情。角蛋白是上皮发育的表型标记物， 分化和致病状态。首席调查员和她 同事们产生的数据表明，某些荷尔蒙和维生素，如 作为GCs和维甲酸，通过直接调节角蛋白基因的表达 它们的核受体。首席研究人员发现，GC受体 使用一种新的机制来调节角蛋白基因的表达。在这 关于提案，首席调查员希望界定和描述 正是这种新奇的机制。在提案中，首席调查员 计划表征GC受体和Gc受体之间的分子相互作用 角蛋白基因上受体的识别位点。其次，她计划 确定参与这些活动的GC受体的特定区域 受体与基因的相互作用。第三，她希望定义共同监管者(其他 相互作用蛋白)参与GC受体和 角蛋白基因。首席调查员认为计划中的实验 将产生新的见解和知识，以提供对 重要的转录因子GC受体的作用机制 角蛋白基因的表达，特别是它在皮肤中的作用。这是一项新的 知识可能导致开发出更好的治疗方法 皮肤病是一种更有效的治疗方法，副作用较少 影响，并有针对性地解决疾病的原因，而不仅仅是 缓解症状。

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.