Marjana Tomic-Canic, PhD

Research

The Biology of Wound Healing

Skin belongs to the unique group of tissues that have the capacity for its own regeneration (epidermis) and repair (dermis). When a wound occurs, the biological process of wound healing activates many cells at the site of injury resulting in migration, vascularization and cell division, thus closing the gap and repairing the injury. Thus, cells at the site of injury release multiple molecules termed growth factors and cytokines, which in turn regulate specific gene expression. These genes produce the effector-molecules that guide and govern the cellular process of wound healing. Understanding molecular mechanisms of wound healing and its pathogenesis in skin may also be applied and utilized in other tissues, such as bone, tendon or cartilage.

The overall goal of our translational program in wound healing is to understand the molecular and cellular mechanisms of tissue repair and regeneration in skin and its pathogenesis, by integrating knowledge at the bench with clinical outcomes at the bedside. This includes identifying which molecular and cellular mechanisms are utilized during normal, acute wound healing process and identifying what molecular events lead to wound healing impairment in chronic (non-healing) wounds and further, developing local sustained gene delivery mechanisms for their treatment. Consequential to the extended life span of the modern human population and increased prevalence of diabetes, we are faced with epidemic proportions of chronic wounds such as diabetic foot ulcers, pressure (bed) sores and venous ulcers, which are the leading cause of lower-leg amputations in the elderly, as well as in the diabetic populations. In collaboration with the Wound Healing Program and Wound Healing and Vascular Biology Laboratory, under the directorship of Dr Harold Brem at Columbia University College of Physicians and Surgeons we recently identified the first genes (oncogene c-myc and b-catenin pathways) that inhibit healing in human chronic wounds and determine the molecular basis of debridement procedure.

Molecular Mechanisms of Cutaneous Wound Healing

This project focuses on identification of the regulators of normal wound healing, such as corticosteroids and retinoids, understanding molecular mechanisms of their action and how they regulate the wound healing process. We have developed experimental model in which we use human skin organ cultures to study the effects of wound healing regulators and their specific role in this process.

Wound Genome Project

The primary goal of this research is to determine a specific group of genes responsible for inhibition of healing in patients with chronic wounds and identify molecular markers that can be utilized as prognostic and diagnostic indicators of clinical outcomes. We quantify changes in gene expression using large scale microarray technology and correlate our findings with clinical outcomes (rate of healing). The synergy of genomics with clinical outcomes, will provide a rational basis for prevention and future therapy of chronic wounds and reduce morbidity and mortality associated with chronic wounds.

Molecular Pathology of Chronic Wounds

Our goal is to identify molecular events that lead to development of chronic wounds utilizing patients’ biopsies and genomics approach as well as molecular, biochemical and cellular biology techniques. We grow primary cells from patients’ biopsies to functionally evaluate our findings.  Our interests are defining the role of aging, neuropathy, obesity and diabetes in development of chronic ulcers.

From Bench to Bedside: Topical Gene Delivery Mechanisms

Genomics approach identifies multiple molecules as potential targets for therapeutic intervention in treatment of chronic wounds. The focus of this project is to utilize novel technologies of topical, sustained release of combination of growth factors that will accelerate the healing of chronic wounds in patients. In collaboration with the Wound Healing Program at Columbia University College of Physicians and Surgeons, we are currently developing methodology for topical gene delivery using adenovirus vectors and biodegradable polyanhydride polymers as a paradigm of the local sustained delivery of multiple growth factors at the wound site. 

Appointments

Languages

English

Selected Publications

Brem H and Tomic-Canic M: Cellular and molecular basis of wound healing in diabetes. (2007) Journal of Clinical Investigations 117:5

Brem H., Stojadinovic O., Diegelmann RF., Entero H., Hanflick A., Lee B. and Tomic-Canic M: Molecular Markers in Patients with Chronic Wounds to Guide Surgical Debridement, (2007) Molecular Medicine, 13(1-2) 30-39

Brem H, Tomic-Canic M, Entero H, Hanflik AM, Wang WM, Fallon J, Ehrlich HP: The Synergism of Age and db/db Genotype Impairs Wound Healing (2007) Experimental Gerontology, Jan 31; [Epub ahead of print]

Stojadinovic O, Lee B, Vouthounis C,  Vukelic S, Pastar I, Blumenberg M, Brem H and  Tomic-Canic M: Novel Genomic Effects of Glucocorticoids in Epidermis: Inhibition of Apoptosis, IFNGamma Pathway and Wound Healing along with Promotion of Terminal Differentiation, (2007) Journal of Biological Chemistry, 282(6):4021-34.

Tomic-Canic M., Mamber, SW., Stojadinovic O., Lee B., Radoja N and McMichael J: Streptolysin O enhances keratinocytes migration and proliferation and promotes skin organ culture wound healing in vitro. (2007) Wound Repair and Regeneration 15(1):71-9

Chan E, Merchant A., Fernandez, P, Desai, A, Tung CF, Montesinos MC, Khoa DN, Pillinger MH, Reiss AB, Tomic-Canic M, Chen JF, Schwarzschild MA, Korn JH and Cronstein BN: Adenosine A2A receptors and Dermal Fibrosis; A Pathogenic Role for Adenosine in Diffuse Dermal Fibrosis (2006) Arthritis and Rheumatism, 54(8) 2632-2642

Tomic-Canic, M: Keratinocyte Cross-Talks in Wounds. (2005)Wounds, 17(9):S3-6

Morasso I. M and Tomic-Canic M.: Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. (2005) Biology of the Cell, 97(3):173-83.

Stojadinovic O., Vouthounis, C., Brem., H., Lee B., Fallon, J., Stallcup, M and Tomic-Canic, M: The Role of the β-catenin and c-myc in Pathogenesis of Cutaneous Wound Healing. (2005) American Journal of Pathology, 167(1):59-69

Jho S.H., Im M.J. Vouthounis, C, Lee, B., Stojadinovic O., Brem, H. Merchant A. and Tomic-Canic, M.: The Book of Opposites: The role of the nuclear receptor co-regulator proteins in negative regulation by retinoic acid and thyroid hormone receptors. (2005) Journal of Investigative Dermatology  124(5):1034-43

Lee, B., Im, M.J., Vouthounis G., Stojadinovic O., Brem H. and Tomic-Canic, M.: From Enhanceosome to Repressosome: Molecular Antagonism between Corticosteroids and EGF that Leads to Inhibition of Wound Healing. (2005)Journal of Molecular Biology  4;345(5):1083-97

Marjana Tomic-Canic and Harold Brem: Gene array Technology and Pathogenesis of Chronic Wounds. (2004) American Journal of Surgery,  188(1A Suppl):67-72.

M. A. Mahajan, S. Das, H. Zhu, M. Tomic-Canic and H.H. Samuels: The nuclear hormone receptor co-activator NRC is a pleiotropic modulator affecting growth, development, apoptosis, reproduction, and wound repair.  (2004) Molecular and Cell Biology  24(11):4994-5004

Radoja, N., Stojadinovic O, Waseem A, Tomic-Canic M, Milisavljevic V, Teebor S, Blumenberg M.: K15 to the Rescue of Basal Keratinocytes: the Elements of Transcriptional Regulation. (2004) Molecular and Cell Biology  24(8):3168-79

A.Gazel, P. Ramphal, M. Rosdy, B. De Wever, N. Hosein, B. Lee,  M.Tomic-Canic and M.Blumenberg.: Transcriptional profiling of epidermal keratinocytes: comparison of genes expressed in skin, cultured keratinocytes and artificial skin equivalents using large DNA microarrays. (2003) Journal of Investigative Dermatology  121: 1459-68

H. Brem, M. Tomic-Canic, A. Tarnovskaya, P. Ehrlich, K. Gill, M. Carasa, S. Weinberger; E. Baskin-Bey  and Entero, H: Healing of Elderly Patients with Diabetic Foot, Venous Stasis  and Pressure Ulcers.  (2003) Surgical Technology International  11:161-7.

H. Brem, J. Young, M. Tomic-Canic, C. Isaacs, T. Bloom and H. P. Ehrlich: Clinical Efficacy and Mechanism of Human Skin Equivalent in Treatment of Diabetic Foot Ulcers. (2003) Surgical Technology International   11:23-31.