This application proposes training in transcriptional regulation of normal and diseased epidermis, focusing on the Grainyhead transcription factor Grhl3 and its role in barrier repair in a mouse model of psoriasis. Grhl3 is an evolutionarily conserved transcriptional activator required for epidermal differentiation in species as divergent as flies and mammals. In addition, Grhl3 plays a role in two distinct aspects of wound healing: migration of keratinocytes and repair of the epidermal barrier. Recent unpublished experiments from the Andersen laboratory have shown that Grhl3 is required for repair of lesions in a psoriasis mouse model. To follow up on these observations, I hypothesize that A) Grhl3 is a critical regulator of the barrier repair process after immune-mediated epidermal injury, and B) some of the barrier genes that normally responses to Grhl3 are unable to do so in psoriasis due to epigenetic changes. To test these ideas, I propose two Specific Aims: 1) To identify candidate epigenetic changes in psoriasis-like epidermis that can inhibit barrier gene activation by Grhl3. 2) To validate the effect of repressive epigenetic changes on selective genes in inflamed epidermis. This research plan is innovative because it focuses on relatively understudied areas, the role of epigenetics and the epidermis in an immune mediated disease, psoriasis. The research is significant as it may provide new understanding of transcriptional regulation of barrier genes in health and disease;the work may ultimately lead to new ideas for treatment and disease activity markers. Through this research plan, and the planned coursework, I will acquire expertise in epidermal biology, barrier repair, genomics, bioinformatics, transcriptional regulation, epigenetics, as well as in state of the art approaches in gene regulation, including RNA-seq, ChIP-seq and MethylCap-seq. These are all new areas of research for me. In addition, several other components of the training plan prepare me for obtaining an independent, academic research position, which is my ultimate goal.
|Klein, Rachel Herndon; Stephens, Denise N; Ho, Hsiang et al. (2016) Cofactors of LIM Domains Associate with Estrogen Receptor Î± to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function. J Biol Chem 291:13271-85|
|Spitler, Ryan; Ho, Hsiang; Norpetlian, Frederique et al. (2015) Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing. J Biomed Opt 20:051022|
|Gordon, William M; Zeller, Michael D; Klein, Rachel H et al. (2014) A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia. J Clin Invest 124:5205-18|