Micro-RNA Molecules as Regulators of Diabetic Wound Healing

Micro-RNA 分子作为糖尿病伤口愈合的调节剂

基本信息

批准号：
8413654
负责人：
Marjana Tomic-Canic
金额：
$ 44.61万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413654
关键词：
Acute Address Affect Amputation Apoptosis Area Autoimmune Diseases Bioinformatics Biopsy Cardiovascular system Caring Cell Proliferation Cells Characteristics Chronic Clinical Complement Complications of Diabetes Mellitus Computer Analysis Dermal Development Diabetic Foot Ulcer Diagnostic Double-Stranded RNA Economic Burden Failure Fibroblasts Functional RNA Future Gene Expression Gene Targeting Genes Genomics Goals Growth Healed Health Human Impaired wound healing Impairment In Situ Hybridization In Vitro Individual Intervention Kidney Laboratories Lead Lower Extremity Malignant Neoplasms Marketing Measures Mediating Messenger RNA Methods MicroRNAs Modeling Molecular Molecular Profiling Mus Neurologic Nucleotides Oligonucleotides Organogenesis Osteomyelitis Pain Pathogenesis Pathway interactions Patients Personal Satisfaction Persons Pharmaceutical Preparations Phenotype Play Preclinical Testing Predisposition Primary Cell Cultures Process Psoriasis Quality of life RNA Interference Recombinants Regulation Research Role Science Sepsis Skin Soft Tissue Infections Testing Therapeutic Therapeutic Agents Tissues Translational Repression Validation Varicose Ulcer Wound Healing angiogenesis base diabetic diabetic wound healing effective therapy healing improved in vivo in vivo Model interest mRNA Expression mRNA Transcript Degradation new therapeutic target novel platelet-derived growth factor BB prevent repaired research clinical testing small molecule therapeutic target wound

Acute Address Affect Amputation Apoptosis Area Autoimmune Diseases Bioinformatics Biopsy Cardiovascular system Caring Cell Proliferation Cells Characteristics Chronic Clinical Complement Complications of Diabetes Mellitus Computer Analysis Dermal Development Diabetic Foot Ulcer Diagnostic Double-Stranded RNA Economic Burden Failure Fibroblasts Functional RNA Future Gene Expression Gene Targeting Genes Genomics Goals Growth Healed Health Human Impaired wound healing Impairment In Situ Hybridization In Vitro Individual Intervention Kidney Laboratories Lead Lower Extremity Malignant Neoplasms Marketing Measures Mediating Messenger RNA Methods MicroRNAs Modeling Molecular Molecular Profiling Mus Neurologic Nucleotides Oligonucleotides Organogenesis Osteomyelitis Pain Pathogenesis Pathway interactions Patients Personal Satisfaction Persons Pharmaceutical Preparations Phenotype Play Preclinical Testing Predisposition Primary Cell Cultures Process Psoriasis Quality of life RNA Interference Recombinants Regulation Research Role Science Sepsis Skin Soft Tissue Infections Testing Therapeutic Therapeutic Agents Tissues Translational Repression Validation Varicose Ulcer Wound Healing angiogenesis base diabetic diabetic wound healing effective therapy healing improved in vivo in vivo Model interest mRNA Expression mRNA Transcript Degradation new therapeutic target novel platelet-derived growth factor BB prevent repaired research clinical testing small molecule therapeutic target wound

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项目摘要

DESCRIPTION (provided by applicant): The objective of this project is to use a genomics approach to identify and demonstrate that specific microRNA molecules impede wound healing in diabetic individuals, thus indicating their potential as novel therapeutic targets. This projet responds to RFA-NR-12-002 by addressing following areas of research interest: a) Elucidation of the genomic markers/mechanisms related to chronic wound susceptibility, development, progression, and repair~ b) Development and testing of genomic based interventions aimed at preventing chronic wounds and/or expediting the healing process. Diabetic foot ulcers (DFUs) are one of the major complications of diabetes mellitus leadin to lower extremity amputation for thousands of diabetic persons each year. Thus, there is a critical unmet need for specific and effective therapeutics to improve healing of these chronic wounds. miRNAs constitute non-coding genomic species that regulate gene expression through post-transcriptional gene silencing and can be neutralized with synthetic small-molecule drugs. Preliminary studies in our laboratory identified a set of miRNAs that are selectively over-expressed in chronic wounds, inhibit acute wound healing in vivo, and may represent potential therapeutic targets. The goals of this project are to test the hypothesis that induction of DFU-specific miRNAs causes healing impairment by repressing genes that coordinate wound healing process, and to determine if targeting them with antagomirs (sequence-specific anti-miRNA oligonucleotides) reverses the healing impairment. Aim 1 is to characterize inhibition of healing in vitro and in vivo by miRNAs identified as induced in DFU patients by quantifying miRNAs in tissue biopsies from DFUs, and using the DFU-induced miRNAs to reconstruct the chronic DFU in acute experimental wounds in mice. Aim 2 is to define the functional role of DFU-specific miRNAs by using synthetic antagomirs to target DFU-specific miRNAs and reverse the non-healing phenotype in primary cell cultures generated from patients' DFU biopsies and in the mouse wound healing model in vivo. Aim 3 is to identify DFU-specific miRNAs and determine their downstream targets specific for wound healing process by genomics approach of quantifying simultaneously mRNA and miRNA gene expression profiles of DFU biopsies. New miRNAs that are identified by this approach will be validated by the methods of Aims 1 and 2. These studies are novel and significant in applying established miRNA strategies and bioinformatics analysis to the problem of validating potential new therapeutic targets for chronic DFUs. Successful completion of this project will lead to future studies to develop candidate therapeutics through preclinical and clinical testing. PUBLIC HEALTH RELEVANCE: This project applies recent breakthroughs in the genomics science of micro RNA (miRNA) to test if targeting specific miRNA molecules by their synthetic mimics and/or antagomirs in actual patients' wound cells in vitro and mouse wound model in vivo may reverse non-healing characteristics. Successful completion of this project will result in identification of a new class of therapeutic candidates, miRNA molecules, that are responsible for the healing inhibition in chronic diabetic foot ulcers .

描述（由申请人提供）：该项目的目的是使用基因组学方法来识别并证明特定的microRNA分子阻碍了糖尿病患者的伤口愈合，从而表明它们是新的治疗靶标的潜力。该ProJET通过解决以下研究领域来对RFA-NR-12-002做出反应：a）阐明与慢性伤口敏感性，发育，进展和修复有关的基因组标记/机制/机制的开发和测试〜）旨在防止慢性伤口和/或旅行的基于基因组的干预措施。糖尿病足溃疡（DFUS）是每年成千上万的糖尿病患者糖尿病铅蛋白降低下肢截肢的主要并发症之一。因此，对于改善这些慢性伤口的愈合的特定和有效治疗剂的至关重要的需要。 miRNA构成非编码基因组物质，通过转录后基因沉默来调节基因表达，可以用合成小分子药物中和。我们实验室的初步研究确定了一组miRNA，这些miRNA在慢性伤口中有选择性表达，抑制体内急性伤口愈合，并可能代表潜在的治疗靶标。该项目的目标是检验以下假设：DFU特异性miRNA的诱导通过抑制协调伤口愈合过程的基因，并确定是否将它们靶向它们是否用Antagomirs（序列特异性抗MIRNA寡核苷酸）靶向损害。目的1是通过量化来自DFU的组织活检中的miRNA，并使用DFU诱导的miRNA在小鼠中急性实验伤口中重建慢性DFU，并使用DFU患者的miRNA鉴定为DFU患者诱导的miRNA对DFU患者诱导的miRNA进行抑制。目的2是通过使用合成的Antagomirs来靶向DFU特异性miRNA，并逆转患者DFU活检和VIVO小鼠伤口愈合模型中的原代细胞培养物中的非愈合表型来定义DFU特异性miRNA的功能作用。 AIM 3是通过基因组学方法同时量化DFU活检的基因组学方法来鉴定DFU特异性miRNA并确定其针对伤口愈合过程的下游靶标。该方法确定的新miRNA将通过目标1和2的方法来验证。这些研究在应用已建立的miRNA策略和生物信息学位分析方面是验证慢性DFU的潜在新治疗靶标的问题。该项目的成功完成将导致未来的研究，通过临床前和临床测试开发候选治疗剂。公共卫生相关性：该项目在微RNA的基因组学科学（miRNA）中采用了最新的突破来测试是否通过其合成模拟物和/或antagomirs在体内的体外和小鼠伤口模型中靶向特定的miRNA分子。成功完成该项目将导致在鉴定新的一类治疗候选物，miRNA分子，这些分子是慢性糖尿病足溃疡的愈合抑制作用。