Chronic and acute wound healing disorders represent a serious health problem that affects more than 8 million people in this country. As a basic scientist with a nursing background, I am devoting a major portion of my research to the understanding of the regulatory mechanisms coordinating the complex process of wound healing in the epidermis. This proposal focuses on understanding the role and regulation of epidermal genes and their products in cutaneous wound healing. Current knowledge of the effect of epidermal gene regulators on wound healing consists of patches of information, each focused on a specific individual gene or regulator, without defining the global picture. Very little is known about the interconnectedness of regulators and their target genes, their interactions and synchronization of functions that lead keratinocytes through one of their vital tasks - wound healing. For example, we have found that glucocorticoid hormones, important regulators of epidermal growth, differentiation and homeostasis, inhibit wound healing and immune responses. We found that their biological effects are mediated through a specific molecular mechanism that blocks the signals of another group of wound healing regulators, proinfiammatory cytokines/growth factors, such as TNF/EGF. In order to develop more effective treatments for chronic wounds, while minimizing side effects, which is my long-term goal, we need to understand first what regulates this process in normally healing epidermis. To achieve this goal, we have developed a wound healing model system using organ cultures of human skin and the novel technology of global transcriptional analysis by gene arrays. Specifically, we shall: 1. identify and characterize the processes and molecular events that occur during wound healing in epidermis by profiling changes in gene expression; 2. define how glucocorticoids and retinoids regulate the epidermal genes that participate in the wound healing process; and 3. explore the possibility and define the role of local hormone production during wound healing. The knowledge and insights gained from these experiments will provide us with a global transcriptional map of the normal wound healing process in epidermis. This knowledge should serve as a basis for determining the causes of chronic wounds and ultimately developing better treatments derived at the molecular level for use in human wounds.
| Jozic, Ivan; Vukelic, Sasa; Stojadinovic, Olivera et al. (2017) Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3?/?-catenin Pathway to Inhibit Wound Closure. J Invest Dermatol 137:1144-1154 |
| Stojadinovic, Olivera; Pastar, Irena; Nusbaum, Aron G et al. (2014) Deregulation of epidermal stem cell niche contributes to pathogenesis of nonhealing venous ulcers. Wound Repair Regen 22:220-227 |
| Vukelic, Sasa; Stojadinovic, Olivera; Pastar, Irena et al. (2011) Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J Biol Chem 286:10265-75 |
| Vukelic, Sasa; Stojadinovic, Olivera; Pastar, Irena et al. (2010) Farnesyl pyrophosphate inhibits epithelialization and wound healing through the glucocorticoid receptor. J Biol Chem 285:1980-8 |
| Pastar, Irena; Stojadinovic, Olivera; Krzyzanowska, Agata et al. (2010) Attenuation of the transforming growth factor beta-signaling pathway in chronic venous ulcers. Mol Med 16:92-101 |
| Lee, Ding-Dar; Stojadinovic, Olivera; Krzyzanowska, Agata et al. (2009) Retinoid-responsive transcriptional changes in epidermal keratinocytes. J Cell Physiol 220:427-439 |
| Brem, Harold; Kodra, Arber; Golinko, Michael S et al. (2009) Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing. J Invest Dermatol 129:2275-87 |
| Golinko, Michael S; Joffe, Renata; de Vinck, David et al. (2009) Surgical pathology to describe the clinical margin of debridement of chronic wounds using a wound electronic medical record. J Am Coll Surg 209:254-260.e1 |
| Tomic-Canic, Marjana; Ayello, Elizabeth A; Stojadinovic, Olivera et al. (2008) Using gene transcription patterns (bar coding scans) to guide wound debridement and healing. Adv Skin Wound Care 21:487-92;quiz 493-4 |
| Harsha, Asheesh; Stojadinovic, Olivera; Brem, Harold et al. (2008) ADAM12: a potential target for the treatment of chronic wounds. J Mol Med 86:961-9 |
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