Epidermal Genes and Their Regulators in Wound Healing

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DESCRIPTION (provided by applicant): 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.