This application directly responds to several objectives outlined in the RFA NR15-001. Specifically, it addresses the role of bacterial colonization of chronic wounds; impact of bioburden on repair process; mechanisms associated with chronic wounds. The objective of this project is to determine the role of antimicrobial molecule, Perforin-2 (P-2) in wound infection and wound healing and to optimize P-2 levels to either prevent or more rapidly resolve bacterial wound infections and speed healing. Wound infection is one of the most frequent complications representing one of the leading causes of lower leg amputations in patients suffering from chronic non-healing wounds, such as diabetic foot ulcers (DFUs).Thus, there is an urgent need to develop new approaches that prevent and treat infected wounds, especially those caused by antibiotic- resistant microorganisms. Our preliminary data suggest that skin cells are equipped to fight infections by expressing high levels of P-2, an antimicrobial protein with unique properties to kill intracellular bacteria. Also, down-regulation of P-2 in healing impaired wounds may contribute to chronic infections and inhibition of healing. We hypothesize that P-2 is necessary for the wound healing process, i.e. barrier maintenance and restoration and further, that the aberrant down-regulation of P-2 plays a role in infection propagation and healing inhibition. To test this we will: assess differential expression f P-2 in DFUs and correlate P-2 expression with healing outcomes (Aim 1); Determine how presence or absence of P-2 in primary HEK and dermal fibroblasts HDF grown in low and high glucose concentration, thus mimicking DFU environment, will affect their ability to kill intracellular bacteria.
(Aim 2); identify the role of P-2 in acute human wound healing.
(Aim 3). This project will provide important data and new knowledge towards understanding mechanisms by which P-2 expression contributes to protection from infection and P-2's role in non-healing wounds (DFUs). This project may provide the basis for development of novel modes for prevention of infection or treatment regimens and potentially simultaneously accelerate wound healing, both of which would have a major clinical impact and significance in both the acute and chronic wound infections. We anticipate that successful completion of this project will lead to future studies to develop candidate therapeutics through preclinical and clinical testing.
Wound infection is one of the most frequent complications in the acute care setting and along with impaired wound healing is a major cost to the health care system. Our long term goal of this research proposal is to understand mechanisms by which human skin fights infection and participates in wound healing and to use this knowledge to develop novel therapeutic approaches to prevent and treat infected wounds.
|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|
|Stone, Rivka C; Stojadinovic, Olivera; Rosa, Ashley M et al. (2017) A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers. Sci Transl Med 9:|
|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|
|Stone, Rivka C; Pastar, Irena; Ojeh, Nkemcho et al. (2016) Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res 365:495-506|
|McCormack, Ryan M; de Armas, Lesley R; Shiratsuchi, Motoaki et al. (2015) Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria. Elife 4:|
|Ramirez, Horacio A; Liang, Liang; Pastar, Irena et al. (2015) Comparative Genomic, MicroRNA, and Tissue Analyses Reveal Subtle Differences between Non-Diabetic and Diabetic Foot Skin. PLoS One 10:e0137133|
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