Aristidis Veves

Personal Information
Title Professor
Expertise Wound Healing
Institution Beth Israel Deaconess Medical
Data Summary
Grants/SubContracts 3
Progress Reports 2
Publications 0
Protocols 0
Committees 3
Experiments 0
Strains 0
Models 0


Clinical and Biochemical Biomarkers to Predict DFU Healing
Diabetic foot problems represent one of the major diabetes complications that significantly impair the quality of life of diabetic patients and lead to more than 750,000 new diabetic foot ulcers (DFU) and 70,000 lower extremity amputations per year in the USA alone. One of the major reasons that have impeded the development of new treatments is the lack of biomarkers that could act as surrogate endpoints in clinical trials and would allow the conduction of clinical trials that are of shorter duration and therefore, of considerably reduced cost. In addition, reliable biomarkers can be used in daily clinical applications to guide the selection of patients for new advanced, and also expensive, treatments and the frequency of application of such treatments. Our unit has a long tradition in conducting research to identify biomarkers related to the management of the diabetic lower extremity. Initial studies showed that changes in ulcer size over a 4-week period can predict very accurately the patients who are going to fail to heal their DFU. Subsequent studies investigated the predictive role of inflammatory cytokines and growth factors and showed that increased serum CRP, GM-CSF, IL-1a, sVCAM, VEGF, IL-17a, IFN?, Substance P, sICAM, IL-2, IL-8 and IL-23 are associated with failure to heal DFU. Finally, in collaboration with a startup company, we have shown that medical hyperspectral technology (HT), a novel diagnostic scanning technique that can quantify tissue oxy- and deoxyhemoglobin can predict diabetic foot ulcer healing. The main aim of the current application is to further explore the development of imaging and biochemical markers that can predict DFU healing and can be used as surrogate endpoints in clinical trials. In addition, another important aim is to develop a local consortium that will include physicians and researchers from local teaching and community hospitals that will participate in the anticipated large clinical trial that will follow. The first aim will employ a newly designed handheld, battery operated, portable device (The HyperView, HyperMed Inc.) to develop algorithms that can predict DFU healing. The second aim will focus on developing multiplex assay panels which will measure previously identified cytokines and growth factors that are associated with DFU healing and develop prognostic algorithms. Finally, in the third aim we will compare the above techniques with the predictive value of changes in the DFU size over a 4-week period. By the end of the application, we will have developed the above two techniques to be ready for use for the main clinical trial. Questions that are expected to be addressed include their sensitivity and specificity, cost effectiveness, ease to use and acceptance by the practicing physicians. Furthermore, a consortium will be developed that will include physicians and researchers for teaching and community hospitals that will be ready to participate in the large clinical trial that will follow.

Proteomic and Transcriptomic Single Cell Analysis In DFU Patient
Numerous cell types are involved in the pathogenesis of impaired wound healing in Diabetic Foot Ulceration (DFU). Previous studies in our unit have focused on endothelial and vascular smooth cells, endothelial progenitor cells, inflammatory cells, fibroblasts, macrophages and mast cells in both animal and human diabetes studies. In ongoing studies, we have also performed transcriptome and epigenome profiling on bulk foot and forearm tissue from patients with healed and non-healed DFU. Finally, we have recently generated single cell transcriptome profile from foot skin of DM and non-DM subjects and diabetic mice. Overall, our data indicate: A: Animal Studies: 1) Inflammation is increased in the pre-injured skin, which is characterized by infiltration of inflammatory cells, increased M1/M2 macrophage ratio and increased expression of inflammatory cytokines; 2) Global transcriptomic and systems biology studies identified pathways and master gene regulators related to inflammation as the major markers associated with improved wound healing; B: Human Studies: 1) Proinflammatory changes in the skin that confirm the association of chronic inflammation with impaired healing of diabetic foot ulcers (DFU); 2) Transcriptomic analysis identified considerable similarities in the pathways and master gene regulators associated with wound healing in DM mice. More specifically, the integrative systems biology analysis indicated key role of inflammation & immune pathways such as TREM1 signaling and dendritic cell maturation and associated MRs (e.g. CD40, IL1, IL6, NF?B) in wound healing; 3) Single cell transcriptome analysis in DFU patients identified activation of highly connected cohesive network of inflammatory and angiogenesis related master regulators (e.g., STAT3, IL15, HIF1?). Furthermore, similar analysis in DM patients without DFU identified activation of additional master regulators (e.g. SMAD3, CD44, TGF?). Overall, our data support the currently accepted consensus that inflammation plays an important role in the development of impaired diabetic wound healing. However, to further understand the pathophysiology of impaired diabetic wound healing, it is mandatory not only to understand the transcriptional state of individual cells at the skin and blood level but also their proteome state. A combined understanding of single cell transcriptome and proteome levels has the potential to greatly enhance our understanding in an agnostic way, as required by the current Collaborative Pilot Program, regarding the interaction of individual cells in the expression of various genes and production of proteins associated with wound healing. In this application, we propose to compare single cell transcriptome and proteome profiling of cells from forearm and foot skin biopsies and blood from healthy, non-DM subjects and DM patients with healed and non-healed DFU. Our main aim will be to evaluate differences in gene expression in various cell types and how this is related to protein expression. We hypothesize that diabetic patients with impaired wound healing will have aberrant gene and protein expression that will lead to a chronic inflammation stage that precludes linear progression to the next phases of wound healing. To this end, we first propose to evaluate single cell gene expression changes in foot and forearm skin specimens and blood immune cells in patients with healed and non-healed DFU, DM patients with no DFU and healthy, non DM patients. We will employ scRNA-seq to perform targeted single cell transcriptome profiling and identify differences with special emphasis on inflammatory and immune pathways. We then propose to evaluate protein expression in the same skin and blood specimens. We will evaluate single cell protein expression. More specifically, we will evaluate the expression of proteins know to be expressed in specific cells and involved in the wound healing process. In addition, in an agnostic way, we will compare the expression of the most highly expressed proteins among the various groups.

Single cell transcriptome sequencing of diabetic foot skin
Chronic wounds, including diabetic foot ulceration and venous ulcers, are a major problem that is associated with significant morbidity and mortality and financial cost. Recent studies by our unit and elsewhere have shown that chronic inflammation is one of the major factors that is associated with impaired wound healing2-4. Wound healing requires a well-coordinated action by numerous cell types, including neutrophils, monocyte/macrophages, fibroblasts, endothelial cells and keratinocytes. However, there is considerable lack of understanding of the molecular physiology of each of these cells that could lead to understanding of the pathophysiology of impaired wound healing. In this application, we propose to perform single-cell transcriptome sequencing from forearm and foot skin biopsies from healthy subjects and diabetic patients with foot ulcer. Our main will be to evaluate gene expression in various cell types and also explore possible differences in various body sites using highly robust drop-seq sequencing approach that allow evaluation of transcriptomic state of thousands of human cells in single experiment by measuring 4,000-7,000 genes. Finally, we will explore possible differences between diabetic and non-diabetic patients. Successful completion of this application will not only contribute to the development of a reference atlas of skin cells transcriptome state but can also play a major role in the development of new therapeutic approaches.

Progress Reports

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