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Member Profile

Marjana Tomic-Canic

Personal Information
Title Professor
Expertise Wound Healing
Institution University of Miami - Medical Campus
Data Summary
TypeCount
Grants/SubContracts 3
Progress Reports 0
Publications 0
Protocols 0
Committees 1
Experiments 0
Strains 0
Models 0

SubContract(s)


Cortisol synthesis enzyme, CYP11B1, as tissue biomarker for diabetic foot ulcers
We plan to develop a robust clinical trial aimed at extending our preliminary observations and further validating CYP11B1 as a biomarker associated with progression and healing of diabetic foot ulcers (DFUs). Based on strong scientific data and extensive preliminary evidence from previous clinical trials, we have selected the cortisol pathway as significantly associated with healing outcomes. Specifically, we propose the cortisol synthesis enzyme CYP11B1 as a tissue biomarker of interest. Our data show that the levels of CYP11B1 correlate with DFU healing outcome. We hypothesize that cortisol in the tissue of neuropathic and neuroischemic DFUs can serve as a predictive biomarker of healing outcomes in patients receiving standard of care treatment for their DFUs, and may serve as a therapeutic target for intervention or to inform treatment decisions. Our collaborative international team of experienced and renowned physicians and scientists has generated one of the largest DFU tissue biomarker data sets and tissue banks that will be utilized in this planning proposal. In order to prepare for this significant undertaking we will plan for the larger biomarker grant by outlining two specific aims: Aim 1 will create an administrative core which will develop the future clinical trial including investigator and site selection, clinical and laboratory methodologies, data collection and storage, investigative approach and logistics in preparation for a large clinical multi-center study of biomarkers for prediction of responsiveness to treatment of neuropathic and neuroishemic DFUs. In the Aim 2 we will optimize methodology and confirm reproducibility of CYP11B1 measurement, established from previous collaborative work in patients receiving standard care. This planning grant will allow our team to conduct a well designed multicenter trial to show the utility of tissue derived cortiosol marker CYP11B1 to predict the healing of DFUs encountered in clinical practice and therefore determine if changes in tissue cortisol status can be used as a targeted therapeutic intervention.

Local and Systemic Biomarkers for Diabetic Foot Ulcers
The proposed work is perfectly aligned with the overall mission of Diacomp: to advance the study of diabetic complications. This project is focusing on testing biomarkers associated with progression and healing, by using minimally-invasive technologies that will facilitate wound management and increase the understanding of biological factors associated with progression, and repair of one of the most debilitating complications of diabetes, diabetic foot ulcers (DFUs). The goal of this P&F project is to validate if recently identified, specific, objective, quantitative miRNA biomarkers 1) correlate with healing outcomes for DFUs and 2) if they have predictive power of early diagnostics of healing outcome. Chronic non-healing DFUs are a prevalent, serious clinical problem with high rates of morbidity, disability and mortality, including a high risk for lower limb amputations. Despite high level of treatment efforts, over 50% of patients with DFU fail to heal with standard care. Ability to differentiate patients who will heal with standard care from patients who are at risk for DFU-associated complications and require early advanced therapy is critical to advancing wound care practice. This will allow targeted therapy and early intervention that will improve healing outcomes, reduce the risk for osteomyelitis, amputation and decrease costs of care. In this project, we will validate previously identified miRNAs that are unique for DFUs and that, in a small sample size in preliminary data, show indication that they differentiate healing from non-healing clinical outcome. Such biomarkers that can objectively and quantifiably distinguish healing from non-healing DFUs for both predictive and diagnostic purposes will have high clinical significance and impact. In a preliminary study enrolling 10 patients with DFUs we performed comprehensive genomic analyses and found 177 significantly de-regulated miRNAs, when compared to diabetic foot (un-ulcerated) skin controls. Of those, 50 were found uniquely present in DFUs but not in acute human wounds. When we compared 3 healing (DFUs closed >55%) and 3 non-healing patients (DFUs closed <45%) we identified a subset of 14 miRNAs that are correlating with healing outcomes. In an independent study it has been shown that specific miRNAs are uniquely found in circulation (plasma) of DFU patients, but the correlation with clinical outcomes of healing was not determined. Therefore, the goal of this project is to validate these unique miRNAs in both tissue and blood, i.e. test if quantification of their expression is correlated with objective quantitative measures of DFU wound closure by testing 20 patients in a clinical study. Patients with Type 2 diabetes will be recruited and tissue/blood samples will be collected during routine debridement at the initial clinic visit and at a follow-up visit 4 weeks later. The extent of wound closure at 4 weeks will be used as a surrogate outcome for non-healing. Wounds that are at least 55% closed by week 4 will be classified as healing wounds. Aim 1 will validate which of the miRNA’s expression correlates with non-healing and which correlate with healing. Aim 2 will test if baseline expression of miRNAs can predict which ulcer will heal and which will not. miRNA expression will be quantified by qPCR. Successful completion of this pilot project has a potential to identify systemic and tissue-specific biomarkers that correlate with clinical outcomes, a first step before this can be brought to randomized multi-center clinical trials. In addition, having a systemic marker will provide major advantage for rapid point-of-care diagnostics that may alleviate a need for tissue samples. Data from this project have the potential for very high impact since they can reform clinical care practices for DFUs by providing the first validated, objective quantitative systemic and/or local biomarker(s) that can be used to: predict which DFUs are not likely to heal with current therapy and therefore require intervention; identify DFUs that have been surgically cleared of non-healing tissue and therefore are more likely to respond to biological therapies; and provide markers that can be used as determinants of success in future clinical trials. Aligned with multiple objectives of the NIDDK and Diacomp missions this project will build the scientific foundation for clinical practice and prevention of disability associated with non-healing DFUs.

Predictive and diagnostic biomarkers for diabetic foot ulcers
The proposed work is uniquely aligned with DiaComp goals as it will advance collaborative studies on diabetic foot ulcers (DFU) a major diabetes-associated complication to identify predictive and diagnostic biomarkers. The goal of the project is to validate previously identified, specific, objective, quantitative tissue biomarkers that correlate with healing outcomes for DFUs. The proposed planning phase will allow optimization of the operational protocol for the future multi-center clinical trial. In a following large clinical trial, we propose to validate previously identified c-myc and ß-catenin as tissue biomarkers that can objectively and quantifiably distinguish healing from non-healing DFUs for both predictive and diagnostic purposes. Chronic non-healing DFUs are a prevalent, serious clinical problem with high rates of morbidity, disability and mortality, including a high risk for lower limb amputations. Ability to differentiate patients who will heal with standard care from patients who are at risk for DFU-associated complications and require early advanced therapy is critical to advancing wound care practice. This will allow targeted therapy and early intervention that will improve healing outcomes, reduce the risk for osteomyelitis, amputation and decrease costs of care. In a pilot study enrolling 25 patients with DFUs we found that increased nuclear presence of c-myc in DFU epidermis correlates with healing impairment. Nuclear ß-catenin shows similar trend. Therefore, the overall goal is to validate these two tissue protein markers, i.e. test if nuclear f c-myc and/or ß-catenin is correlated with objective quantitative measures of DFU wound closure in a multi-center clinical trial. We propose the planning phase that will establish and tests the functionality operational components required for clinical trial. Aim 1 will develop a Core Management Plan that will design and prepare the implementation and oversight of clinical, research and biostatistical aspects of large clinical trial for biomarker(s) validation. Aim 2 will perform a “test run” to implement standardization and logistics of the experimental approach on prospectively enrolled 10 patients with DFUs. We will utilize collaborative teams from Winthrop Hospital and University of Miami Wound Centers to evaluate shipment, quality assessment of debridement specimens and time to quantification (optimizing staining and quantification protocols). Added benefit from these samples will be to increase existing data set and prospectively confirm findings that c-myc % nuclear presence correlates with non-healing and can predict non-healing DFUs. It will also increase sample size to confirm if the trend of correlation of the ß-catenin to clinical outcomes indeed shows statistical significance. Successful completion of project will reform clinical care practices by providing the first validated, objective quantitative tissue biomarker(s) that can be used to: predict which DFUs are not likely to heal with current therapy and therefore require intervention; identify DFUs that have been surgically cleared of non-healing tissue and therefore are more likely to respond to biological therapies; and provide markers that can be used as determinants of success in future clinical trials.


Progress Reports

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Annual Reports

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No experiments found.

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