The healing of skin involves an ordered cascade of events that bears a potentially significant relationship to morphogenetic processes including embryological epithelial fusion. In fact, these two processes may share common factors to close holes and form seams. One potential factor is Interferon Regulatory Factor 6 (IRF6). Previously, IRF6 was shown to be essential for the development of the lip and palate in humans. The objective of this proposal is to evaluate Irf6 in cutaneous wound healing. In support of this hypothesis, Irf6 was shown to be necessary for skin development, and regulate differentiation and proliferation of keratinocytes, the epithelial cell type in skin and palate. Our long term goal is to understand the role of IRF6 in morphogenesis and tissue repair. The central hypothesis for our project is that proper wound healing requires appropriate spatial and temporal expression of Irf6. Our initial inspiration for this proposal is that Van der Woude patients, who have a mutation in IRF6, are more likely to have a worse outcome following surgical repair of cleft than individuals with cleft lip or palate (and have two non-mutated copies of IRF6). Subsequently preliminary data showed that 1) induction of Irf6 expression in the palate requires Tgfb3, a gene involved in scar-free wound healing 2) Irf6 is expressed in the spinous layer of the epidermis, 3) Irf6 regulates keratinocyte differentiation and proliferation, 4) Irf6 regulates expression of Krt14 and Krt17, keratins known to be involved in wound healing, and 5) keratinocytes from mice deficient for Irf6 have impaired migration in vitro. Thus, our data suggests that Irf6 is at the fulcrum between two pathways known to be involved in wound healing, Tgfb signaling and intermediate filaments, and supports the hypothesis that Irf6 is essential for wound healing.
In Specific Aim 1, we will determine the spatial and temporal expression of Irf6 during normal cutaneous wound healing, and test whether this expression requires Tgfb3.
In Specific Aim 2, we will determine the role of Irf6 in wound healing in vitro and in vivo, taking advantage of human and murine tissues and cells. Successful completion of these studies will increase our understanding of one of the mechanisms by which the body closes holes and forms seams following injury and during development. This will provide opportunities to identify therapeutic targets for wound healing, and perhaps also to intervene and correct abnormalities that originate from a failure in embryonic fusions. This proposal will evaluate the role of Interferon Regulatory Factor 6 in cutaneous wound healing, a major cause of rising health-related costs. We hope to better understand how body closes holes and forms seams following injury and during development. ? ? ?
|Aerts, Andrea; DeVolder, Ian; Weinberg, Seth M et al. (2014) Haploinsufficiency of interferon regulatory factor 6 alters brain morphology in the mouse. Am J Med Genet A 164A:655-60|
|Smith, Brian J; Nidey, Nichole; Miller, Steven F et al. (2014) Digital imaging analysis to assess scar phenotype. Wound Repair Regen 22:228-38|
|Gutierrez, Jeydith A; Hannoush, Zeina C; Vargas, Luis G et al. (2013) A Novel non-sense Mutation in Keratin 10 Causes a Familial Case of Recessive Epidermolytic Ichthyosis. Mol Genet Genomic Med 1:108-112|
|Biggs, Leah C; Rhea, Lindsey; Schutte, Brian C et al. (2012) Interferon regulatory factor 6 is necessary, but not sufficient, for keratinocyte differentiation. J Invest Dermatol 132:50-8|
|Le, Mark; Naridze, Rachelle; Morrison, Jasmine et al. (2012) Transforming growth factor Beta 3 is required for excisional wound repair in vivo. PLoS One 7:e48040|
|Carr, Wanakee J; Oberley-Deegan, Rebecca E; Zhang, Yuping et al. (2011) Antioxidant proteins and reactive oxygen species are decreased in a murine epidermal side population with stem cell-like characteristics. Histochem Cell Biol 135:293-304|
|Schatteman, Gina C; Awad, Ola; Nau, Eric et al. (2010) Lin- cells mediate tissue repair by regulating MCP-1/CCL-2. Am J Pathol 177:2002-10|
|Jones, Jodi L P; Canady, John W; Brookes, James T et al. (2010) Wound complications after cleft repair in children with Van der Woude syndrome. J Craniofac Surg 21:1350-3|
|Beaty, Terri H; Murray, Jeffrey C; Marazita, Mary L et al. (2010) A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42:525-9|