GLUCOCORTICOIDS IN EPIDERMIS: MECHANISMS OF ACTION

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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.