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 .

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Research Project (R01)
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Special Emphasis Panel (ZNR1)
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Tully, Lois
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
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Ramirez, Horacio A; Pastar, Irena; Jozic, Ivan et al. (2018) Staphylococcus aureus Triggers Induction of miR-15B-5P to Diminish DNA Repair and Deregulate Inflammatory Response in Diabetic Foot Ulcers. J Invest Dermatol 138:1187-1196
Rubio, Gustavo A; Elliot, Sharon J; Wikramanayake, Tongyu C et al. (2018) Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing. J Cell Physiol 233:5503-5512
Sawaya, Andrew P; Pastar, Irena; Stojadinovic, Olivera et al. (2018) Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. J Biol Chem 293:1439-1449
Lukic, Jovanka; Chen, Vivien; Strahinic, Ivana et al. (2017) Probiotics or pro-healers: the role of beneficial bacteria in tissue repair. Wound Repair Regen 25:912-922
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Glinos, George D; Verne, Sebastian H; Aldahan, Adam S et al. (2017) Optical coherence tomography for assessment of epithelialization in a human ex vivo wound model. Wound Repair Regen 25:1017-1026
Hamdan, Suzana; Pastar, Irena; Drakulich, Stefan et al. (2017) Nanotechnology-Driven Therapeutic Interventions in Wound Healing: Potential Uses and Applications. ACS Cent Sci 3:163-175
Liang, Liang; Stone, Rivka C; Stojadinovic, Olivera et al. (2016) Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions. Wound Repair Regen 24:943-953
Pastar, Irena; Stojadinovic, Olivera; Sawaya, Andrew P et al. (2016) Skin Metabolite, Farnesyl Pyrophosphate, Regulates Epidermal Response to Inflammation, Oxidative Stress, and Migration. J Cell Physiol 231:2452-63
Lindley, Linsey E; Stojadinovic, Olivera; Pastar, Irena et al. (2016) Biology and Biomarkers for Wound Healing. Plast Reconstr Surg 138:18S-28S

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