Trp63 in limbal stem cell deficiency

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Project Summary 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.