The Role of Snai2/Slug in Diabetes-impaired Wound Healing

Impaired wound healing is a common complication of diabetes mellitus. Advanced glycation end products (AGEs) are a consequence of diabetes and are formed from non-enzymatic reactions between glucose and proteins. The accumulation of AGEs is believed to disrupt wound repair and alter protein function. The epidermal growth factor receptor (EGFR) and a downstream effector, Snai2/Slug, are key regulators of reepithelialization, a vital component of wound healing. Reepithelialization requires keratinocyte proliferation and migration. Therefore, we examined the impact of AGEs on these EGF-stimulated responses. In this dissertation, I present evidence for a critical role of Snai2 in diabetes-impaired wound reepithelialization, extending the knowledge of Snai2 past normal wound repair. A well-studied AGE precursor, glyoxal, was used to model a diabetic environment. Glyoxal decreased EGF-stimulated EGFR activation, leading to impaired keratinocyte proliferation and migration in cell culture and in tissue explants. EGF-stimulated and basal Snai2 protein levels decreased following glyoxal treatment, and this decrease was prevented by the glycation inhibitor, aminoguanidine. Snai2 immunoprecipitated from glyoxal-exposed cells was modified by the AGE product carboxymethyl lysine, identifying Snai2 as an intracellular target of glycation. Furthermore, mice over-expressing Snai2 demonstrated enhanced epithelial outgrowth compared to wild type mice when exposed to glyoxal ex vivo. These data represent a significant breakthrough in the field of diabetes and wound healing as it is the first evidence linking Snai2 down-regulation by pathophysiologic stimuli to impairments in reepithelialization. In addition, few intracellular proteins have been identified as targets of glycation, and this work highlights Snai2 as a novel nuclear protein target with demonstrated relevance to diabetic healing. With this knowledge, we may explore methods to pharmacologically induce Snai2 protein to promote healing of diabetic wounds.Biomedical SciencesDoctoralUniversity of New Mexico. Biomedical Sciences Graduate ProgramHudson, Laurie G.Felton, LindaMcGuire, PaulOzbun, Michell