New diabetic wound healing model to functionally analyze human genetic variation
Diabetes mellitus currently affects almost 400 million people worldwide including over 25 million adults in the United States. Impaired wound repair is a major diabetic complication contributing to the morbidity and mortality associated with a lifetime of diabetes. New model systems that permit real-time in vivo interrogation of wound response dynamics under diabetic conditions would help drive this field forward. To this end, we have developed a genetic beta cell ablation model to achieve constitutive beta cell destruction in zebrafish. In this setting we established an epithelial wounding assay and discovered a leukocyte recruitment defect in diabetic animals. It is still unclear which genetic and environmental factors determine susceptibility to diabetic complications in diabetic patients. GWAS has identified TNFAIP3 (A20) as a major candidate gene for multiple inflammatory and autoimmune diseases as well as diabetic complications, although the biological function of most disease associated variants remains unknown. In this proposal we have three specific aims: Aim 1) Determine whether neutrophil responses and/or recruitment signals are defective under diabetic conditions. Aim 2) Test whether normalizing glucose levels is sufficient to rescue neutrophil migration. Aim 3) Use zebrafish models to elucidate the function of human A20 variants. This pilot project will establish a novel in vivo screen for genetic factors that drive impaired wound healing. These studies will set the stage for high-throughput functional analysis of genetic variation that is emerging from human GWAS and sequencing studies focused on diabetes and its complications.

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