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Alleviating Reactive Carbonyl Species-Induced Progenitor Cell Dysfunction in Diabetic Wound Healing

减轻糖尿病伤口愈合中反应性羰基物质诱导的祖细胞功能障碍

基本信息

批准号：
10445242
负责人：
TERRENCE J. MONKS
金额：
$ 37.48万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-02 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445242
关键词：
Address Adenovirus Vector Adult Advanced Glycosylation End Products Affect American Amino Acids Amputation Animal Model Animals Attenuated Binding Blood Vessels Bone Marrow Cell Count Cell Therapy Chronic Data Detection Diabetes Mellitus Diabetic Foot Ulcer Endothelium Energy Metabolism Engineered Gene Enzymes Functional disorder Gene Transfer Generations Glucose Goals Health Homing Human Impaired wound healing Impairment In Vitro Innovative Therapy Inositol Knockout Mice Knowledge Lactoylglutathione Lyase Mediating Methodology Modification Molecular Mutate Organ Outcome Study Patients Pilot Projects Plasma Play Proteins Proteomics Protocols documentation Pyruvaldehyde Refractory Regimen Reporting Research Reticulum Ribonucleases Role Site Stress System Technology Testing Therapeutic Therapeutic Effect Tissues Type 2 diabetic Ulcer adduct angiogenesis base biological adaptation to stress chronic wound db/db mouse diabetic diabetic patient diabetic ulcer diabetic wound healing efficacy testing endoplasm endothelial stem cell functional loss gain of function genetic manipulation glycation healing improved in vivo liquid chromatography mass spectrometry loss of function neovascularization non-healing wounds novel novel therapeutic intervention novel therapeutics overexpression precursor cell prevent progenitor response sensor skin wound stem cell function stem cell therapy stem cells therapeutic development therapeutic target therapy design tissue repair wound wound closure wound healing wound treatment

项目摘要

PROJECT SUMMARY Refractory wounds in diabetic patients often result in amputation. Bone marrow derived endothelial progenitor cells (EPCs) actively participate in wound repair through angiogenesis after homing to the wounding site. However, progenitor cell functions are impaired in diabetes with mechanisms poorly understood. Reactive carbonyl species (RCS) are the intermediates and by-products generated during energy metabolism. Our pilot studies demonstrate one of the most potent RCS and the major precursor of the advanced glycation endproducts (AGE), methylglyoxal (MGO), exerted immediate inhibitory effects on progenitor cell functions in vitro. The glyoxalase I (GLO1), the key enzyme detoxifying MGO, was deficient in diabetic EPCs. These observations unveil an important message: Theses RCS actually play a major role in compromising progenitor cell function in diabetes, and this is due to the deficient glyoxalase defense system. The Major Goal of this project is to understand the molecular mechanisms of disrupted angiogenesis induced by RCS and to identify therapeutic targets for diabetic wound repair. Our recent report has demonstrated that an endoplasm reticulum response sensor, Inositol-Requiring Enzyme 1α (IRE1α), is essential to progenitor cell-mediated angiogenesis during wound repair. The endothelial-specific deletion of IRE1α leads to aberrant wound angiogenesis in vivo. However, how IRE1α functionality in EPCs is damaged in diabetes is not clear yet. Our pilot data strongly suggest that MGO directly diminishes IRE1α’s ribonuclease (RNase) function, and that IRE1α activation in EPCs is severely inhibited by MGO but rescued by GLO1 over-expression. We further found out that chronic wounds in diabetic animals started to heal upon receiving GLO1 gene transfer in vivo. Based on these findings, we propose Central Hypothesis that accumulated MGO in diabetes compromises progenitor cell function via interfering with IRE1α function, resulting in disrupted angiogenesis and delayed wound healing. To test the hypothesis, we propose Three Specific Aims: 1) Elucidate mechanisms by which MGO causes EPC dysfunction and IRE1α deficiency in diabetes in vitro; 2) Determine the molecular basis for MGO-induced IRE1α deficiency in vitro; 3) Determine the therapeutic effects of lowering MGO in diabetic wound healing in vivo. Our proposed studies will use newly developed Liquid chromatography–mass spectrometry (LC-MS) protocol to quantify free MGO accumulation in human plasma and diabetic foot ulcer tissues, representing the first effort to acquire the dynamic changes of free MGO generation in the microenvironment. We will employ both gain-of-function and loss-of-function technologies for gene manipulations, IRE1α gene engineered animals, and a newly established chronic diabetic wound animal model with cell therapies. Our project will allow us to uncover novel molecular mechanisms of impaired angiogenesis and wound healing in diabetes in which RCS-induced progenitor cell dysfunction is playing a pivotal role. Findings from this project will provide valuable information for novel therapeutics development for diabetic wound healing by augmenting RCS scavenger GLO1 or ER stress response sensor IRE1α.