Marjana Tomic-Canic

Personal Information
Title Professor
Expertise Wound Healing
Institution University of Miami - Medical Campus
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Data Summary
Grants/SubContracts 3
Progress Reports 4
Publications 1
Protocols 0
Committees 2

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.
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.
A Pilot Study to Develop New Therapy Approach for Diabetic Foot Ulcers
Diabetic foot ulcers (DFU) represent a major clinical and scientific problem that demands solutions. DFUs affect more than 6 million Americans, significantly reduces their quality of life, carries a high mortality due to associated complications, burdening health care system with costs over $20 billion. Despite urgent need for new effective therapies no new efficacious therapy was approved for past 20 years. Therefore, we propose this innovative pilot project to pre-clinically test a new strategy in the cell-based therapy that involves catalase-modified diabetic adipocyte-derived stem cells (ASCs) and their exosomes. One major contributor to impaired healing, are the hormonal changes associated with diabetes and aging. A key factor associated with the gradual change in hormones is enhanced oxidant stress as evidenced by decreased expression of superoxide dismutase and catalase. Recent studies have shown that mesenchymal stem cells derived from diabetic and elderly individuals have similar phenotype, including increased oxidative stress and impaired regenerative capability that precludes their use as autologous therapy. Our preliminary data suggest that reversing oxidant stress in aging ASCs by the knock-in of catalase improves their ability to promote wound healing, while knock-down of catalase in young ASCs renders the young ASC repair phenotype ineffective. Thus, we propose the hypothesis that catalase replete diabetic ASCs will promote tissue repair by restoring a healthy ASC oxidant status. We will test our hypothesis using DFU 3D organoid human skin wound models that utilizes primary cells derived from DFU patients. Aim 1 fill focus to determine whether catalase replete diabetic ASCs achieve reprogramming of the delayed healing using 3D DFU human organoid culture whereas Aim 2 will evaluate therapeutic potential of exosomes derived from catalase replete ASCs. The goal of this project is to pre-clinically test the novel strategy to convert diabetic ASCs and their exosomes into potent therapy that promotes healing of DFUs, which will provide novel therapeutic strategy for patients suffering from diabetic foot ulcers.

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Year: 2018; Items: 1

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