The transcription factor TP63 (human)/Trp63 (mouse), referred to as ?p63? in this application, is a key regulator for the development of stratified epithelia. Mice that completely lack p63 expression fail to develop stratified epithelia, including the corneal epithelium. However, p63 is also required to maintain and repair stratified epithelia postnatally. This is underscored by the clinical phenotype of patients suffering from ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome [EEC; OMIM #604292], a disorder caused by mutations in the p63 gene. EEC patients develop limbal stem cell deficiency (LSCD), a condition that is characterized by progressive corneal erosions, corneal conjunctivalization, and ultimate loss of vision. Besides a clear causal link between p63 abnormalities and LSCD, essentially nothing is known regarding the molecular and cellular mechanisms that underlie the mutant p63-dependent pathology. Further, it is not known which cell compartment(s) in the eye are affected by EEC. We hypothesize that normal p63 function is required to maintain limbal stem cells (LSC) and to drive proper differentiation of these cells into corneal epithelial cells. To test this hypothesis, we propose to use a combination of genetically engineered mouse models and in vitro cell culture models to identify mutant p63-controlled gene regulatory pathways in the ocular epithelium. This approach will not only advance basic knowledge of cornea epithelial stem cell biology, it will also point to molecular pathways that could be targeted therapeutically in patients suffering from LSCD caused by impaired p63 function.

Public Health Relevance

The main goal of this application is to understand the function of the transcription factor p63 in limbal stem cells and to elucidate how abnormal p63 function, which is observed in patients suffering from ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC), can lead to cornea erosions, corneal conjunctivalization, and subsequent loss of vision.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EY029081-01A1
Application #
9822288
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
2019-08-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
1
Fiscal Year
2019
Total Cost
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