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.

糖尿病性皮肤溃疡（DU）是一种主要的医疗保健负担，已知会导致截肢。据估计，所有糖尿病患者中有15-20%在其生命周期中会出现皮肤伤口。这些包括创伤引起的伤口和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。大多数这些皮肤伤口是复杂的，成为慢性的，并由外科和皮肤科提供者照顾。据估计，只有一半的溃疡性皮肤伤口的所有糖尿病患者生存超过五年后，他们的最初表现。这项工作的灵感来自于观察到单核苷酸变异（SNV）是使个体易患糖尿病并发症的重要遗传因素。SNV可能参与与序列特异性转录因子的串扰，并影响DNA甲基化，这可能使伤口闭合所需的基因表达沉默。基于糖尿病溃疡患者的初步基因分型研究，确定了超过17，000个SNV。基因本体分析确定了53个与伤口上皮形成相关的含SNV基因。NOTCH 1基因是糖尿病溃疡的主要信号转导中心，在糖尿病患者伤口边缘组织中富集了两个NOTCH 1特异性SNV，即转录起始位点rs 10870081和rs34485221。SNV在伤口闭合中的意义尚不清楚。拟议的工作旨在系统地研究SNV及其与慢性伤口患者糖尿病伤口闭合的相关性。从所提出的纵向队列研究中收集来自相同患者的SNV、超甲基化和愈合轨迹数据的组合方法可能在糖尿病伤口愈合学科中建立新的范例。系统的以患者为基础的DU基因组研究很少，拟议的工作旨在为伤口愈合研究提供一种新的范式。提出了以下具体目标：目标1。在糖尿病溃疡患者中，确定导致伤口闭合受损的SNV。1.1糖尿病依赖性SNV与受损的伤口闭合相关。将鉴定受此类SNV影响的基因座，并测试其在伤口闭合中的显著性。1.2在伤口闭合受损的情况下，以上鉴定的糖尿病依赖性SNV的功能意义由相应基因座的超甲基化状态确定。