Dominant mutations in p63, a transcription factor expressed as six isoforms, underlie the skin fragility syndrome ankyloblepharon ectodermal dysplasia and defting (AEG). Skin erosions that resemble those found in AEG patients develop in mice with reduced Delta-Np63 expression. The proposed studies will dissect the regulatory pathways by which Delta-Np63 controls normal epidermal homeostasis and will provide insight into the disease mechanism underlying AEG. We have recently identified Fras1 and Galml4 as direct transcriptional targets of Delta-Np63. Misexpression of these genes may contribute to the AEG phenotype. To further study the role of these genes in embryonic and postnatal skin, we will develop mouse models in which the expression of these genes is altered. These mouse models will allow us to determine the role of Frasi in regulating basement membrane integrity in postnatal epidermis. Furthermore, we will use these mouse models to determine the role of Calml4 in epidermal terminal differentiation. Our analysis of Calml4 function in keratinocyte terminal differentiation will be completed by performing proteomics and microarray analysis. Ultimately, the proposed studies will contribute to our understanding of the molecular mechanisms that cause skin fragility in AEG patients, and may identify targets for novel therapeutic approaches aimed at treating this disease.

Public Health Relevance

Skin erosions in patients with a skin fragility disease, AEG syndrome, are caused by mutations in a gene called p63. We have recently developed a mouse model for this disease which will allow us to determine how defects in p63 cause skin erosions. These studies may lead to the development of novel therapeutic strategies for this disease and other diseases characterized by fragile skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Transition Award (R00)
Project #
5R00AR054696-05
Application #
8082625
Study Section
Special Emphasis Panel (NSS)
Program Officer
Baker, Carl
Project Start
2009-09-14
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$249,000
Indirect Cost
Name
University of Colorado Denver
Department
Dermatology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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