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

• 批准号: 8850720
• 负责人: Marjana Tomic-Canic
• 金额: $ 39.99万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850720
• 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; Future; Gene Expression; Gene Targeting; Genes; Genomic approach; 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; Untranslated RNA; Validation; Varicose Ulcer; Wound Healing; angiogenesis; base; diabetic; diabetic wound healing; effective therapy; healing; improved; in vivo; in vivo Model; interest; limb amputation; mRNA Expression; mRNA Transcript Degradation; new therapeutic target; novel; platelet-derived growth factor BB; prevent; repaired; research clinical testing; small molecule; therapeutic target; wound

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.

描述（由申请人提供）：该项目的目标是使用基因组学方法来识别和证明特定的 microRNA 分子阻碍糖尿病个体的伤口愈合，从而表明它们作为新治疗靶点的潜力。 该项目通过解决以下研究兴趣领域来响应 RFA-NR-12-002：a）阐明与慢性伤口易感性、发展、进展和修复相关的基因组标记/机制〜b）开发和测试基于基因组的干预措施，旨在预防慢性伤口和/或加速愈合过程。 糖尿病足溃疡（DFU）是糖尿病的主要并发症之一，每年导致数千名糖尿病患者截肢。因此，对于改善这些慢性伤口的愈合的特定且有效的治疗方法存在着迫切的未满足的需求。 miRNA 构成非编码基因组物种，通过转录后基因沉默调节基因表达，并可以用合成小分子药物中和。我们实验室的初步研究发现了一组在慢性伤口中选择性过度表达、抑制体内急性伤口愈合的 miRNA，并且可能代表潜在的治疗靶点。 该项目的目标是测试以下假设：诱导 DFU 特异性 miRNA 通过抑制协调伤口愈合过程的基因而导致愈合损伤，并确定使用 antagomir（序列特异性抗 miRNA 寡核苷酸）靶向它们是否可以逆转愈合损伤。 目标 1 是通过量化 DFU 组织活检中的 miRNA，并使用 DFU 诱导的 miRNA 重建小鼠急性实验伤口中的慢性 DFU，来表征在 DFU 患者中诱导的 miRNA 对体外和体内愈合的抑制作用。 目标 2 是通过使用合成的 antagomir 靶向 DFU 特异性 miRNA 来定义 DFU 特异性 miRNA 的功能作用，并逆转患者 DFU 活检产生的原代细胞培养物和小鼠体内伤口愈合模型中的不愈合表型。 目标 3 是通过同时量化 DFU 活检的 mRNA 和 miRNA 基因表达谱的基因组学方法，识别 DFU 特异性 miRNA 并确定其伤口愈合过程特异的下游靶点。通过这种方法鉴定的新 miRNA 将通过目标 1 和 2 的方法进行验证。这些研究对于将已建立的 miRNA 策略和生物信息学分析应用于验证慢性 DFU 潜在新治疗靶点的问题具有新颖性和重要意义。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疗法。

项目成果

Quality assessment of tissue specimens for studies of diabetic foot ulcers.

用于糖尿病足溃疡研究的组织标本的质量评估。

• DOI: 10.1111/exd.12104
• 发表时间: 2013
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Stojadinovic,Olivera;Landon,JenniferN;Gordon,KatherineA;Pastar,Irena;Escandon,Julia;Vivas,Alejandra;Maderal,AndreaD;Margolis,DavidJ;Kirsner,RobertS;Tomic-Canic,Marjana
• 通讯作者: Tomic-Canic,Marjana

Optical coherence tomography for assessment of epithelialization in a human ex vivo wound model.

• DOI: 10.1111/wrr.12600
• 发表时间: 2017-11
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Glinos GD;Verne SH;Aldahan AS;Liang L;Nouri K;Elliot S;Glassberg M;Cabrera DeBuc D;Koru-Sengul T;Tomic-Canic M;Pastar I
• 通讯作者: Pastar I

Probiotics or pro-healers: the role of beneficial bacteria in tissue repair.

• DOI: 10.1111/wrr.12607
• 发表时间: 2017-11
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Lukic J;Chen V;Strahinic I;Begovic J;Lev-Tov H;Davis SC;Tomic-Canic M;Pastar I
• 通讯作者: Pastar I

Clinical application of growth factors and cytokines in wound healing.

• DOI: 10.1111/wrr.12205
• 发表时间: 2014-09
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Barrientos S;Brem H;Stojadinovic O;Tomic-Canic M
• 通讯作者: Tomic-Canic M

Staphylococcus aureus Triggers Induction of miR-15B-5P to Diminish DNA Repair and Deregulate Inflammatory Response in Diabetic Foot Ulcers.

• DOI: 10.1016/j.jid.2017.11.038
• 发表时间: 2018-05
• 期刊: The Journal of investigative dermatology
• 作者: Ramirez HA;Pastar I;Jozic I;Stojadinovic O;Stone RC;Ojeh N;Gil J;Davis SC;Kirsner RS;Tomic-Canic M
• 通讯作者: Tomic-Canic M