Cell Specific Gene Editing to Close Diabetic Wounds

细胞特异性基因编辑闭合糖尿病伤口

基本信息

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
项目类别：
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

项目摘要

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) 是一项重大的医疗负担，据估计，15-20% 的糖尿病患者在其一生中都会出现皮肤伤口，其中包括外伤造成的伤口和计划手术造成的伤口。值得注意的是，DFU 的 5 年死亡率高于大多数癌症，其中大多数皮肤伤口都很复杂，变成慢性伤口，并且估计只有一半由外科和皮肤科医生治疗。患有溃疡性皮肤伤口的糖尿病患者在首次出现症状后可以存活五年以上，这项研究的灵感来自于这样的观察：单核苷酸变异（SNV）是导致个体出现糖尿病并发症的重要遗传因素，并且可能与这些因素相互影响。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 53。与伤口上皮化相关的 SNV 基因作为与 DU 相关的主要信号传导中心出现，两个 NOTCH1 特异性 SNV，rs10870081 和 rs34485221（NOTCH1 转录起始位点的上游）在人类糖尿病伤口边缘中富集。这项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关系。所提出的从纵向队列研究中收集同一患者的 SNV、高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一个新的范例。工作旨在为伤口愈合研究建立一个新的范式，提出以下具体目标：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 与糖尿病相关的 SNV 相关。受此类 SNV 影响的位点将被识别并测试其在伤口闭合中的重要性。 1.2 在伤口闭合受损的情况下，上述糖尿病依赖性 SNV 的功能意义由相应位点的高甲基化状态决定。。