Elucidating the role of nonessential amino acid metabolism in diabetic skin wounds

PROJECT SUMMARY Type II diabetes takes a large toll on both individuals and society through morbidity and financial burden. Patients with diabetes are at risk of developing diabetic foot ulcers that are nonhealing and can lead to infections and amputations. The pathophysiology that underlies this impaired wound healing can be due to damage to blood vessels, neurons, and immune function, all of which contribute to delayed wound healing. Normally, skin requires nutrients like nonessential amino acids for building material and energy to undergo repair and heal wounds. My preliminary metabolomics data in different wound regions in control and db/db mice indicate that four nonessential amino acids, including serine and glycine, are particularly depleted in diabetic wounds, suggesting their important biological roles in wound healing. Previous studies of diabetic mice and humans have also found a reduction of serine and glycine within wounds and systemic blood. However, it remains unknown why they are depleted, whether they are required for wound healing, and how they are used for healing. Thus, identification of the cause of their reduction and usage by different cell populations during wound healing in diabetic models will facilitate the future development of new therapeutics. To this end, I will 1) define the distribution and fates of the four nonessential amino acids in different wound regions in healthy and diabetic mice; and 2) determine whether serine and glycine supplementation can promote wound healing. My proposed study will utilize a broad spectrum of innovative tools including in vivo stable isotope tracing coupled with high-resolution mass spectrometry-based metabolomics, microscopy, and cell sorting. This study will expand our understanding of how efficient nutrient utilization facilitates wound healing in normal and diabetic wounds. The findings from this study will also generate important implications regarding potential targets for future pharmacological or genetic knockout experiments in the effort toward developing novel therapies for improving diabetic wound healing.