TP63 is a transcription factor required for the normal development and homeostasis of the skin. The finding that null mutations in the mouse ortholog prevent the development of the epidermis and epidermal appendages supports this conclusion. In humans, missense mutations in the TP63 gene are linked to a subset of severe developmental disorders, termed ectodermal dysplasias (ED). Our application focuses on two EDs, ankyloblepharon ectodermal dysplasia and clefting (AEC) and ectrodactyly ectodermal dysplasia and clefting (EEC), as they each are associated with severe skin erosions. Although EEC has historically no been associated with skin abnormalities, they do occur in a subset of patients (we refer to these patients as EEC/S patients). It is currently not clear how TP63-AEC or TP63-EEC mutations lead to the observed skin defects, specifically abnormalities in keratinocyte differentiation and keratinocyte cell-cell and cell-extracellular matrix adhesion. While a few deregulated genes associated with AEC were described, essentially nothing is known regarding the disease mechanism underlying EEC/S. The main goal of this application is to elucidate the cellular and molecular defects underlying these EDs and to expand our understanding of the role of TP63 in normal keratinocyte biology. We propose to generate ED patient keratinocyte-based skin equivalent models to mimic ED and to elucidate cellular and molecular disease pathways. To generate an unlimited source of genetically defined patient cells for this analysis, we will utilize stem cell technology (induced pluripotent stem cell (iPSC) technology). We will establish the transcriptome and functionally test the role of deregulated genes in AEC and EEC/S keratinocytes. These experiments will yield new mechanistic insights into AEC/EEC disease pathways and establish causal links between TP63 target genes and defects observed in patient skin.

Public Health Relevance

This application focuses on a group of inherited skin diseases termed ectodermal dysplasias (EDs). The EDs investigated are caused by mutations in a major regulator of skin function, TP63. The main goal of this application is to understand the mechanisms by which TP63 mutations cause these severe and currently untreatable skin disorders. The long term goal is to develop new approaches to effectively treat these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AR066713-01
Application #
8927734
Study Section
Special Emphasis Panel (ZRG1-MOSS-U (02))
Program Officer
Baker, Carl
Project Start
2014-09-17
Project End
2016-08-31
Budget Start
2014-09-17
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$458,099
Indirect Cost
$154,909
Name
University of Colorado Denver
Department
Dermatology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045