Irx1 regulation of oral tissue repair and maintenance.

Project Summary Oral disease causes a significant burden on overall health and 3.9 billion people are affected worldwide. Oral diseases such as periodontitis, cancer, tooth loss, craniofacial birth defects and pain all affect growth and maintenance of the oral cavity and oral mucosa. Improving oral wound healing due to diseases, chronic wounding and scarring would greatly affect quality of life. The oral mucosa is primed with wound- activated gene signatures to facilitate the rapid and scarless wound healing. However, the genetic and molecular mechanism underlying this process is still largely unknown. We have found that Iroquois Homeobox 1 (IRX1/Irx1) is expressed in the basal layer of gingival epithelium and cell populations in the mesenchyme in both murine and human samples, which indicates its potential role in regulating gingival wound healing. Moreover, Irx1 expression may mark potential stem cell niches in the basal cell layer of the oral epithelium. We are investigating the role of Irx1 in epithelial basal cells during gingival wound healing utilizing our mouse gingival injury model. We have previously reported that Irx1 is expressed lung stem cells. By analyzing the wound healing progression and lineage tracing of basal cell activity during gingival wound healing, our preliminary data suggests that re-epithelialization is negatively affected during gingival wound healing in adult Irx1+/- (Het) mice, as indicated by delayed wound closure, delayed structural changes in regenerated epithelium and altered differentiation of keratinocytes. The transcriptomic analysis revealed a wound associated gene signature in the Irx1+/- epithelium. In preliminary studies, Irx1 was identified as a new gene that is primed at the base of the gingiva, which may facilitate rapid and scarless wound healing through the EGF signaling pathway. To determine if Irx1 regulates a progenitor cell niche in the oral cavity we propose three specific aims. 1) Determine the expression pattern of Irx1 during embryogenesis and homeostasis in potential progenitor cell niches in the oral cavity; 2) Identify the role of Irx1 in oral tissues using inducible Cre models for lineage tracing; 3) To analyze the effects of oral wound healing regulated by Irx1.