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Function and Metabolic Properties of Toxic Neutrophils

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Differential expression of inflammatory genes occurs during septicemia, the major morbid and mortal event of patients in non-coronary critical care units. Bacterial constituents like lipopolysaccharide/endotoxin (LPS) initiate septicemia via transcription of acute proinflammatory genes such as IL-1beta and TNFalpha. Thereafter, acute proinflammatory genes are persistently repressed, while expression of anti-inflammatory and chronic inflammatory genes persists. We reported that the differential expression of genes in LPS adapted THP-1 cells and septicemia leukocytes is both signal and gene specific. The objective of this research is to clarify the molecular events controlling differential gene expression during septicemia. We will test the hypothesis that LPS adaptation differentially regulates transcription factors NFkappaB and C/EBP, which in turn, participate in repressing acute proinflammatory genes like IL-1beta and sustaining chronic inflammatory genes like MRP8/10. AIM 1 will examine the regulation of the Rel family transcription factor, p65/RelA and its role in repressing IL-1a transcription in LPS adapted THP-1 cells. AIM 2 will examine the regulation of C/EBP transcription factors and their role in maintaining MRP8/14 transcription in LPS adapted THP-1 cells. Both aims 1 and 2 will employ biochemical and genetic analyses, including chromatin immunoprecipitation (ChIP) assays, electrophoretic mobility shift assays (EMSA), reporter gene assays, protein phosphorylation and mutation analyses, and examine Rel and C/EBP interactions with other transcription regulators that may repress IL-1beta or sustain MRP8/14. AIM 3 extends findings of aims 1 and 2 to LPS adapted primary monocytes and when feasible, to blood leukocytes obtained from humans with septicemia. This research will advance our understanding of the functional genetics of innate immune mechanisms that are associated with septicemia.

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