Defining translational mechanisms to promote regenerative healing of chronic wounds Abstract: Chronic wounds are common among our veterans, often impacting negatively on their ability to achieve a high quality of life as productive members of our society, and the care of these wounds and their sequelae consumes a significant portion of resources within the Veterans Health Administration. The ultimate objective of the research described in this proposal is to develop solutions that allow durable and regenerative healing of these wounds. Patients who are aged and/or diabetic are at major risk for developing difficult non-healing wounds, and diabetes occurs among veterans at about three times the rate of the general US population. To effectively manage these wounds, it is essential to understand the normal healing process and engineer treatments that promote the physical and biochemical environment of healing tissue. Pathologically, our identification of specific subclasses of cells within human skin and how they control skin wound healing carries the potential to ameliorate skin infections and chronic wounds. Our long-term goal is to translate our understanding of the cellular and molecular interactions that drive skin repair into viable treatments for chronic wounds. Our prior work has identified the importance of cytokines and unique cell types including fibroblast subtypes and macrophages in skin wound healing in mice. The overall objective of this translational research proposal is to define the molecular mechanisms by which fibroblast subtypes contribute to wound repair in aged and diabetic skin and how that can be translated into novel treatment modalities for chronic wounds. Our central hypothesis is that fibroblast heterogeneity is essential for proper skin repair after injury and is altered with diabetes and age. This hypothesis is based on our findings that: 1) Multiple classes of fibroblasts contribute to skin repair after injury; 2) Human skin wounds contain multiple fibroblast populations; 3) Wound growth factors such as Igf1 specifically contribute to proliferation of non-fibrotic fibroblast populations in mouse wounds and in vitro and Igf1R expression is altered in diabetes; 4) Specific populations of fibroblasts are lost in aged skin. Based on these preliminary data, our record of discovery in skin wound healing, and our team of experts from plastic surgery and skin cell/developmental biology, we are exceptionally capable of executing the proposed experiments. We plan to objectively test our central hypothesis and obtain the objective of this proposal by pursuing the following specific aims: 1) Determine whether the lack of IGF1R in fibroblasts alters wound healing in mice; 2) Assess the heterogeneity and IGF-1 response of human dermal fibroblast subpopulations in wounds; and 3) Determine whether transplantation of young fibroblasts and/or IGF1 treatment can ameliorate wound healing defects in aged and diabetic mouse skin. We will t...