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Regulation of LPS-Mediated HMGB1 Release by Poly (ADP-Ribose) Polymerase-1

PI: Rajesh Aneja, MD

Funding: NIH/NIGMS R01GM098474 (Project period: 6/1/12 to 5/31/17)

Sepsis continues to be a global public health problem and results in significant mortality and morbidity. Despite advances in the understanding of the mechanisms that govern sepsis, the discovery of new and efficacious therapeutic agents has lagged behind. In this proposal, we will explore the mechanisms involved in the release of High Mobility Group Box-1, a crucial late - mediator of sepsis.

High Mobility Group Box-1 (HMGB1) is a transcription factor-like protein that has recently been characterized as a prototypical Damage -Associated Molecular Pattern molecule (DAMP). HMGB1 is a crucial late-acting mediator of sepsis in patients with sepsis, severe sepsis and septic shock. While much attention has been focused on the function of extracellular HMGB1, the mechanisms of HMGB1 release in sepsis have received little consideration.

The proposed research plan will define the role of PARP-1 in the modulation of lipopolysaccharide (LPS)-mediated HMGB1 transcription, post-translational modification and secretion. The central hypothesis for this grant application is that PARP-1 is essential for LPS-mediated HMGB1 secretion.