The innate immune system is composed of """"""""hard-wired"""""""" elements of immunity, such as natural killer cells, phagocytes, defensins, and complement, that mount an initial protective response to kill, clear and/or limit deleterious invaders. A relatively newly defined family of proteins, designated as defense collagens, is an example of the constitutive recognition components of the innate system. Each of these defense collagens recognizes selective motifs displayed on pathogenic material, and mediates a protective response. Interaction of several soluble defense collagens with a novel transmembrane protein, C1qRP, has been shown to facilitate the rapid ingestion of suboptimally opsonized particles, a potentially critical mechanism in host defense particularly at early stages of infection/disease when little or no adaptive response is yet present. In addition, this receptor, which is selectively expressed on monocytes, macrophages, neutrophils, endothelial cells and platelets, may contribute to the rapid clearance of apoptotic and/or damaged cells, a critical process during tissue remodeling. This would be particularly advantageous, as ligation of this receptor by monocytes does not trigger proinflammatory cytokine production. This proposal will focus, first, on determining the physiologic role of this receptor by generating, characterizing, and testing specific hypotheses in a murine model in which this gene has been ablated, and secondly, on the intracellular signaling mechanisms involved in triggering enhanced phagocytosis and in regulating proinflammatory cytokine induction. The ability of C1qRP to regulate the phagocytic capacity of myeloid cells could be extremely valuable as a prophylactic treatment for individuals at risk for infection, such as individuals with genetic immunodeficiencies or pathogen-induced immunosuppression, patients undergoing cancer chemotherapy, or patients undergoing high risk surgery. However, this surface molecule also has the potential for modulation of processes contributing to damaging inflammation (such as vasculitis, nephritis, neurodegeneration), and understand physiologic clearance of apoptotic cells and/or cellular debris which would be potentially relevant to both inflammation and certain types of autoimmunity.
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