This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Innate immunity serves as an essential first-line of defense against microbial pathogens and also influences the nature of the subsequent adaptive immune response. Phagocytic cells, such as macrophages and neutrophils, play key roles in innate immunity because of their ability to recognize, ingest, and destroy many pathogens by oxidative and non-oxidative mechanisms. These phagocytes express the NADPH oxidase, a multi-protein enzyme complex that generates reactive oxygen species (ROS) during the host immune responses. Although essential to host defense, ROS are highly-reactive and can also damage host tissue. It is therefore essential that we understand the regulatory aspects of the host inflammatory response, in order to define better strategies for controlling inflammation. Recently, we made the exciting observation that the oncogenic transcription factor, PLAGL2, plays a role in the regulation of the NADPH oxidase. Although PLAGL2 has been shown to be involved in carcinogenesis, virtually nothing is known regarding the identity of PLAGL2 target genes or the mechanisms of PLAGL2 gene regulation in vivo and nothing is known about the role of PLAGL2 in phagocytic leukocytes. Based on our studies, we hypothesize that PLAGL2 is an important regulatory component in innate immune responses. The proteomics-based approach outlined in this proposal incorporates 2D-DIGE, 2D-Zdye and LC-MS/MS to elucidate the role of PLAGL2 in phagocytic leukocytes by 1) identifying additional PLAGL2 target genes and the signaling networks involved, and 2) the mechanisms whereby PLAGL2 regulates inflammation via protein-protein interactions. This work aims to lead to a systems biology analysis of the signaling pathways and mechanisms in the host inflammatory response, in collaboration with systems researchers at MSU and Pacific Northwest National Lab (PNNL). Understanding the basic systems biology of the host inflammatory response, as regulated by PLAGL2, is expected to uncover unique regulatory mechanisms that will provide the foundation for the development of improved therapies for influencing inflammation and disease pathogenesis.
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