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

项目总结 II型糖尿病通过发病率和经济负担对个人和社会都造成了巨大的损失。 糖尿病患者有患糖尿病足部溃疡的风险，这种溃疡无法愈合，可能导致 感染和截肢。伤口愈合受损的病理生理学基础可能是 对血管、神经元和免疫功能的破坏，所有这些都会导致伤口延迟愈合。 正常情况下，皮肤需要非必需的氨基酸等营养物质和能量来进行 修复和治愈伤口。对照和db/db组不同创面的代谢组学初步数据 老鼠表明，包括丝氨酸和甘氨酸在内的四种非必需氨基酸在 糖尿病伤口，表明它们在伤口愈合中发挥着重要的生物学作用。先前对糖尿病小鼠的研究 人类还发现伤口和全身血液中的丝氨酸和甘氨酸减少了。然而，它 目前尚不清楚它们为什么会耗尽，它们是否是伤口愈合所必需的，以及它们是如何使用的 为了治愈伤痛。因此，确定不同细胞群体减少和使用它们的原因 糖尿病模型的创面愈合将促进未来新疗法的发展。为此，我将1) 四种非必需氨基酸在健康人体不同创面的分布和命运 2)确定补充丝氨酸和甘氨酸是否能促进伤口愈合。我的 拟议的研究将利用广泛的创新工具，包括体内稳定同位素示踪耦合 以高分辨率质谱学为基础的代谢组学、显微镜和细胞分选。这项研究将 扩大我们对营养有效利用如何促进正常和糖尿病患者伤口愈合的理解 伤口。这项研究的发现也将对潜在的目标产生重要的影响 未来的药理学或基因敲除实验，努力开发新的治疗方法 促进糖尿病伤口愈合。

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.