Phagocytes (polymorphonuclear cells, monocytes/macrophages) constitute the first line of host defense against injections. They play this role effectively through cell surface receptors that recognize common moieties in microbes, and trigger a coordinate a coordinated and self- limited inflammatory response. This includes phagocytosis and release of chemokines and lipid-derived mediators that help engage the adaptive immune response. Dysregulation in positive and negative regulatory loops of this system is responsible for many common diseases. The overall goal of this Project is to elucidate mechanisms of positive and negative regulation of key phagocyte membrane receptors and mediators that underlie the dual role of these cells in the initiation and resolution of the inflammatory response. During the past four years of this Program Project, studies have provided significant new insights into the transcriptional regulation and contribution of these receptors to infection and injury, and into the pro and anti-inflammatory properties of certain phagocyte-derived lipid mediators. Taking advantage of novel tools and model conformation and topology involved in expression of integrin CD11b, and establish the role of newly discovered single- and double- stranded DNA binding factors in the response of myeloid cells to developmental and inflammatory stimuli. The next will use homologous recombinant mice lacking key lipid receptors generated during the previous funding period to investigate the roll of infectious and non- infectious inflammation in the pathogenesis of atherosclerosis. The next takes advantage of the recent discovery that phagocyte-derived lipid mediators have potent mediators in the resolution of local inflammation. The last addresses the critical role of the phagocyte in recruiting and modulating the adaptive immune response, utilizing molecular biology techniques and Drosophila genetics to dissect the chemokine signaling pathways. An administrative core and a molecular and cell scientists with considerable and diverse expertise in many aspects of cell biology, molecular biology, genetics, and centralized Core B, which will provide reagents and technical expertise for all projects. Each of the projects is likely to define critical components in the phagocyte response to its microenvironment, and may provide novel targets for therapeutic interventions. The objectives of this proposal and their common emphasis on molecular mechanisms invite a high degree of collaborative interactions and conceptual synergy that continues to be bested served by the program project format. This platform also provides an important forum for technology transfer and research training in inflammation.
Showing the most recent 10 out of 98 publications
