Complexity and the Wound Healing Response

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Project Summary The ability to heal is essential for human health. The remarkable wound healing capacity of humans (and indeed of all animals) is a complicated process. Genomic studies suggest that more than 5000 mRNA transcripts change expression patterns during wound healing, and more than a dozen cell types participate. Despite the large number of cells and molecules that are involved, many aspects of the complexity of wound healing are not well understood. Systems approaches have established the breadth of genes involved in healing, and have compared gene profiles in different types of wounds. Yet many questions about the networks and interactions within wounds are still unanswered. The research proposed here couples novel quantitative approaches with basic biologic research to examine several questions related to the complexity and diversity of the events that compose tissue repair. The research plan addresses three separate but complementary questions. Question 1 asks - What are the regulatory pathways that underlie the differential, site specific healing that is seen in skin versus oral mucosa? Studies by us and others have shown that wounds in the oral mucosa exhibit faster re-epithelialization, reduced inflammation, a better-developed angiogenic response, and less scar formation as compared to skin. Oral mucosal and skin wounds also have distinctive transcriptomes. The central concept underlying Question 1 is that key transcription factors are responsible for the differential healing seen in these two tissues. The research approach uses state-of-the-art algorithms and in vivo experiments to discover and validate the transcription factors (and their networks) that distinguish oral mucosal and skin healing. Question 2 asks - What is the level of redundancy in healing wounds? This question explores the robustness of healing by assessing molecular redundancy. Redundancy has been posited to exist in wounds as a “fail-safe” mechanism, insuring that wound healing proceeds even if some key elements are functionally inactivated. The underlying concept for Question 2 is that significant gene compensation occurs in wounds when specific genes are deleted. The approach uses genetically deficient (“knockout”) mice to examine the extent of redundancy in healing wounds. Question 3 asks- Can quantitative models be used to predict wound healing outcomes? Our ongoing collaboration utilizes a novel computational modeling framework called the dynamic cellular finite-element model (DyCelFEM) to develop a model of epithelial repair that is predictive of healing responses. The research plan extends the model to include additional features of wound healing, such as angiogenesis. When completed, the model can be used to test the effect of perturbations of single or multiple factors on healing outcomes. This advanced model will be a powerful tool that can contribute to our understanding of both the pathophysiology of chronic wounds and the development of therapeutics. Taken together, the three elements of the research plan address how wound healing is governed at a network level, and will uncover critical features that regulate the ability to heal.