Cell Specific Gene Editing to Close Diabetic Wounds

细胞特异性基因编辑闭合糖尿病伤口

• 批准号: 10628884
• 负责人: Chandan K Sen
• 金额: $ 57.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10628884
• 关键词: Affect; Amputation; Caring; Cells; Chronic; Complication; Complications of Diabetes Mellitus; DNA Methylation; Data; Dermatologic; Diabetes Mellitus; Diabetic Foot Ulcer; Discipline; Fruit; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic study; Genomics; Genotype; Goals; Healthcare; Human; Human Genome Project; Hypermethylation; Impairment; Individual; Knowledge; Longevity; Longitudinal cohort study; Malignant Neoplasms; Morbidity - disease rate; NOTCH1 gene; Nucleotides; Ontology; Operative Surgical Procedures; Patients; Persons; Pharmacotherapy; Positioning Attribute; Prevalence; Provider; Quality of life; Research; Risk; Signal Transduction; Techniques; Testing; Transcription Initiation Site; Trauma; United States National Institutes of Health; Variant; Vision; Work; care burden; chronic wound; cohort; combinatorial; diabetic; diabetic ulcer; diabetic wound healing; epithelial wound; genetic risk factor; genome-wide; healing; lifetime risk; mortality; novel; personalized medicine; skin ulcer; skin wound; transcription factor; wound; wound closure; wound healing

Diabetic skin ulcers (DU) represent a major healthcare burden that is known to lead to amputations. It is estimated that 15–20% of all diabetics develop skin wounds across their lifespan. These include wounds caused by trauma and those caused by planned surgery. Notably, the 5-year mortality rate of DFU is higher than most cancers. Majority of these skin wounds are complicated, become chronic and are cared for by surgical and dermatological providers. It is estimated that only half of all diabetics with ulcerative skin wounds survive more than five years after their initial manifestation. The proposed work is inspired by the observation that single nucleotide variations (SNV) are important genetic factors that predispose an individual to diabetic complications. SNV are likely to engage in crosstalk with sequence-specific transcription factors and influence DNA methylation which could silence gene expression required for wound closure. Diabetic ulcer patient-based preliminary genotyping studies, identified greater than 17,000 SNV. Gene ontology analyses identified 53 SNV-containing genes relevant to wound epithelialization. NOTCH1 gene emerged as a major signaling hub associated with DU. Two NOTCH1 specific SNV, rs10870081 and rs34485221 (upstream of NOTCH1 transcription start site) were enriched in human diabetic wound-edge. The significance of SNV in wound closure remains unknown. The proposed work seeks to systematically study SNV and its association with diabetic wound closure in chronic wound patients. The combinatorial approach of collecting SNV, hypermethylation and healing trajectory data from the same patients from a longitudinal cohort study as proposed is likely to establish a new paradigm in the discipline of diabetic wound healing. Systematic patient-based genomic studies of DU are scanty and the proposed work is aimed at seeding a novel paradigm in wound healing research. The following specific aim is proposed: Aim 1. In patients with diabetic ulcer, identify SNV responsible for impaired wound closure. 1.1 Diabetes-dependent SNVs are associated with impaired wound closure. Loci affected by such SNV will be identified and tested for their significance in wound closure. 1.2 The functional significance of diabetes dependent SNV identified above, in the context of impaired wound closure, is determined by hypermethylation status of the corresponding loci.

糖尿病皮肤溃疡（DU）代表了一项重大的医疗保健燃烧，已知会导致截肢。据估计，所有糖尿病患者中有15-20％在其寿命中会出现皮肤伤口。这些包括由创伤引起的伤口和由计划手术引起的伤口。值得注意的是，DFU的5年死亡率高于大多数癌症。这些皮肤伤口中的大多数是复杂的，变得慢性，并受到外科和皮肤科提供者的照顾。据估计，在最初表现后五年以上，所有糖尿病患者中只有一半的糖尿病患者生存。所提出的工作的灵感来自于观察到的单个核局部变异（SNV）是使人患有糖尿病并发症的重要遗传因素。 SNV可能会与序列特异性转录因子进行串扰，并影响DNA甲基化，这可能会使伤口闭合所需的基因表达沉默。糖尿病性溃疡患者基于患者的初步基因分型研究，发现超过17,000个SNV。基因本体论分析鉴定出与伤口上皮化有关的53个含SNV的基因。 Notch1基因作为与DU相关的主要信号枢纽出现。两个Notch1特异性SNV，RS10870081和RS34485221（Notch1转录起始位点的上游）富含人类糖尿病伤口边缘。 SNV在伤口闭合中的意义仍然未知。拟议的工作旨在系统地研究SNV及其与慢性伤口患者中糖尿病伤口闭合的关联。从纵向队列研究中收集SNV，超甲基化和愈合轨迹数据的组合方法可能会在糖尿病伤口愈合学科中建立新的范式。 DU的系统基于患者的基因组研究很少，拟议的工作旨在播种伤口愈合研究中的新型范式。提出了以下特定目的：目标1。在糖尿病性溃疡患者中，确定造成伤口受损的SNV。 1.1糖尿病依赖性SNV与伤口闭合受损有关。受这种SNV影响的基因座将被鉴定并测试其在伤口闭合中的重要性。 1.2在伤口闭合受损的背景下，依赖糖尿病的糖尿病的功能意义取决于相应基因座的高甲基化状态。