The plasminogen activation system extensively regulates tissue remodeling and both the initiation and resolution of inflammation in a broad range of tissues. Dysregulation of these processes has a broad pathologic impact, including aberrant wound healing (chronic unhealed wounds are a major component of diabetes), lung and cardiovascular fibrosis, scarring, infection, sepsis, and autoimmune disease. A critical gap in knowledge is the understanding of how plasminogen communicates with cells to regulate these processes. The Plg receptor, Plg-RKT, is a novel integral membrane protein that binds plasminogen via a C-terminal lysine exposed on the cell surface and promotes plasminogen activation on the cell surface. The broad, long-term goal of our laboratory is to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes. This proposal is based on new data obtained with Plg-RKT deficient mice that support a pivotal role for Plg-RKT in the regulation of extracellular matrix remodeling and inflammation in physiological and pathological settings, particularly in healing of cutaneous wounds. The objective of this proposal is to define specific steps in the wound healing process at which the activity of Plg-RKT is necessary and to identify mechanisms by which Plg- RKT regulates these specific steps. The central hypothesis to be addressed is that Plg-RKT is necessary to accomplish normal wound healing. To address our hypothesis our specific aims are: (1) to identify specific mechanisms by which Plg-RKT regulates wound healing and (2) to investigate specific mechanisms by which macrophage Plg-RKT regulates inflammation. Wound healing studies will be performed in mice with global deletion of Plg-RKT, mice with either macrophage- or keratinocyte-specific deletion of Plg-RKT, mice with global deletion of both Plg-RKT and fibrinogen, and mice over-expressing Plg-RKT. Wound tissue will be analyzed for Plg accumulation, cytokine induction, and aberrant neutrophil, collagen and fibrin accumulation. In vitro experiments with Plg-RKT-/- and Plg-RKT+/+ macrophages will test the role of macrophage Plg-RKT in plasmin-dependent cytokine release, intracellular signaling and efferocytosis. And a proteomic approach will be used to interogate the Plg-RKT interactome. We expect that accomplishment of our specific aims will establish Plg-RKT as a pivotal regulator of wound healing and provide fundamental insights into how initiation and resolution of inflammation and tissue remodeling are regulated in wound healing. These new insights are expected to have a major impact on the understanding of a broad array of pathological and physiological processes requiring an effective inflammatory response and requiring tissue remodeling. Furthermore, the results to be obtained may identify new potential therapeutic targets for the treatment of diseases with dysregulated tissue remodeling and dysregulated inflammation.
The proposed research is relevant to public health because new knowledge of mechanisms by which extracellular matrix remodeling and inflammation are regulated will be acquired. This knowledge is directly applicable to understanding the broad array of diseases with dysregulated tissue remodeling and dysregulated inflammation, including, including aberrant wound healing, lung and cardiovascular fibrosis, scarring, infection, sepsis, and autoimmune disease. In addition, the results of these studies are expected to identify potential targets for development of new therapies for these diseases.
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