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

阐明非必需氨基酸代谢在糖尿病皮肤伤口中的作用

基本信息

批准号：
10607579
负责人：
Johnny Le
金额：
$ 4.32万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-02 至 2027-03-01
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607579
关键词：
Acceleration Amino Acids Amputation Award Biochemical Biochemical Pathway Biological Blood Blood Vessels Carbon Cell Separation Cell physiology Cells Cessation of life Citric Acid Cycle Consumption Coupled Critical Pathways Data Development Diabetes Mellitus Diabetic Foot Ulcer Diabetic mouse Diet Financial Hardship Functional disorder Future Genetic Glycine Harvest Histology Human Immune Immune response Immunofluorescence Immunologic Impaired healing Impaired wound healing Impairment Individual Infection Investigation Isotopes Knock-out Knowledge Malignant Neoplasms Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Metabolism Methodology Microscopy Modeling Molecular Morbidity - disease rate Mus Muscle satellite cell Neurons Non-Essential Amino Acid Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Requirements Organ Pathway interactions Patients Play Population Process Production Proliferating Protein Biosynthesis Quality of life Resolution Risk Role Route Serine Skin Societies Supplementation Technology Testing Time Tissues amino acid metabolism assault building materials cell type chronic ulcer chronic wound db/db mouse diabetic diabetic ulcer diabetic wound healing experimental study feeding healing immune function improved in vivo infection risk innovation liquid chromatography mass spectrometry metabolomics migration novel novel therapeutics nucleotide metabolism pharmacologic repaired skin barrier skin wound spatiotemporal stable isotope success tool wound wound care wound closure wound environment wound healing

项目摘要

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.

项目概要 II 型糖尿病通过发病率和经济负担给个人和社会造成巨大损失。糖尿病患者有患糖尿病足溃疡的风险，这种溃疡无法愈合，并可能导致感染和截肢。这种伤口愈合受损的病理生理学可能是由于对血管、神经元和免疫功能的损害，所有这些都会导致伤口愈合延迟。通常，皮肤需要非必需氨基酸等营养物质来承受建筑材料和能量修复和治愈伤口。我在对照和db/db中不同伤口区域的初步代谢组学数据小鼠表明，四种非必需氨基酸，包括丝氨酸和甘氨酸，在糖尿病伤口，表明它们在伤口愈合中的重要生物学作用。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。然而，它目前仍不清楚它们为何会被耗尽、伤口愈合是否需要它们以及如何使用它们为了治愈。因此，确定不同细胞群在不同细胞群中减少和使用它们的原因糖尿病模型中的伤口愈合将促进未来新疗法的开发。为此，我将 1) 定义健康和不同伤口区域四种非必需氨基酸的分布和命运糖尿病小鼠； 2）确定补充丝氨酸和甘氨酸是否可以促进伤口愈合。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具有基于高分辨率质谱的代谢组学、显微镜检查和细胞分选。这项研究将扩大我们对有效营养利用如何促进正常和糖尿病患者伤口愈合的理解伤口。这项研究的结果还将对潜在目标产生重要影响未来的药理学或基因敲除实验，旨在开发新的疗法改善糖尿病伤口愈合。