- 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045974-02
Application #
6375204
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$185,357
Indirect Cost
Name
New York University
Department
Dermatology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Vukelic, Sasa; Stojadinovic, Olivera; Pastar, Irena et al. (2010) Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. J Biol Chem 285:1980-8
Lee, Ding-Dar; Stojadinovic, Olivera; Krzyzanowska, Agata et al. (2009) Retinoid-responsive transcriptional changes in epidermal keratinocytes. J Cell Physiol 220:427-439
Tomic-Canic, Marjana; Stojadinovic, Olivera; Lee, Brian et al. (2008) Nexus between epidermolysis bullosa and transcriptional regulation by thyroid hormone in epidermal keratinocytes. Clin Transl Sci 1:45-9
Liovic, Mirjana; Lee, Brian; Tomic-Canic, Marjana et al. (2008) Dual-specificity phosphatases in the hypo-osmotic stress response of keratin-defective epithelial cell lines. Exp Cell Res 314:2066-75
Brem, Harold; Tomic-Canic, Marjana; Entero, Hyacinth et al. (2007) The synergism of age and db/db genotype impairs wound healing. Exp Gerontol 42:523-31
Brem, Harold; Stojadinovic, Olivera; Diegelmann, Robert F et al. (2007) Molecular markers in patients with chronic wounds to guide surgical debridement. Mol Med 13:30-9
Tomic-Canic, Marjana; Mamber, Stephen W; Stojadinovic, Olivera et al. (2007) Streptolysin O enhances keratinocyte migration and proliferation and promotes skin organ culture wound healing in vitro. Wound Repair Regen 15:71-9
Stojadinovic, Olivera; Lee, Brian; Vouthounis, Constantinos et al. (2007) Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation. J Biol Chem 282:4021-34
Lee, Brian; Vouthounis, Constantinos; Stojadinovic, Olivera et al. (2005) From an enhanceosome to a repressosome: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. J Mol Biol 345:1083-97
Jho, Sang H; Vouthounis, Constantinos; Lee, Brian et al. (2005) The book of opposites: the role of the nuclear receptor co-regulators in the suppression of epidermal genes by retinoic acid and thyroid hormone receptors. J Invest Dermatol 124:1034-43

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