DEBRA Research K15 KERATIN TO THE RESCUE OF BASAL KERATINOCYTES IN EPIDERMOLYSIS BULLOSA SIMPLEX: USE OF THYROID HORMONES AND INTERFERON-GAMMA TO INCREASE SPECIFICALLY K15 GENE TRANSCRIPTION

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K15 KERATIN TO THE RESCUE OF BASAL KERATINOCYTES IN EPIDERMOLYSIS BULLOSA SIMPLEX: USE OF THYROID HORMONES AND INTERFERON-GAMMA TO INCREASE SPECIFICALLY K15 GENE TRANSCRIPTION

M. Blumenberg, Ph.D., Principal Investigator.
Department of Dermatology, NYU School of Medicine, New York, USA.

Annual Report, November 2005.

The hypothesis:

Gene replacement therapy for K14 mutations is extremely difficult because of technical difficulties in treating the entire integument. However, increasing the cellular content of K15 could replace the mutant K14 and thus alleviate the skin blisters in patients with EBS. Focused on the regulation of expression of the human K15 gene, we found that interferon-g, IFNg, and thyroid hormone, T3, uniquely and potently induced the K15 promoter {Radoja, 2004}. We followed up these studies with a comprehensive analysis of IFNg-responsive genes in epidermal keratinocytes, and discovered that IFNg inhibits differentiation, causes DNA replication arrest, activates immune responses etc., all of which may cause severe side-effects in treatment of EBS with IFNg {Banno, 2003}.

Specific aims:

Our aim is to characterize the responses of human epidermal keratinocytes to thyroid hormones, a potential treatment for EBS, using Affymetrix oligonucleotide microarrays to identify the T3-regulated genes in human epidermal keratinocytes.

Preliminary results:

We have identified the T3-regulated genes in keratinocytes and listed them according to their biological functions. While the detailed in-depth analysis is ongoing, we are greatly encouraged by our findings! Most importantly for our original hypothesis, we find that T3 regulates a very limited number of genes; this meant that topical treatment of EB patients with T3 should not entail severe side-effects. Especially encouraging is the fact that no oncogenes are induced and no tumor suppressor genes are suppressed by T3, which suggests that the T3-based therapy will be safe and effective.

REFERENCES:

Radoja, N. S., O., Waseem, A., Tomic-Canic, M., Milisavljevic, V. , Teebor, S. and Blumenberg, M. 2004. Thyroid hormones and interferon-gamma specifically increase K15 gene transcription Moll. Cell. Biol. 24:3168-79.

Banno, T., M. Adachi, L. Mukkamala, and M. Blumenberg 2003. Unique keratinocyte-specific effects of interferon-gamma that protect skin from viruses, identified using transcriptional profiling Antivir Ther. 8:541-54.