Brief background of the proposal and its relevance to the CDI’s objectives
Acute lung injury (ALI) is a devastating disease resulting from an insult such as infection. In children,
mortality from ALI accounts for up to 30% of pediatric intensive care unit deaths. Neutrophils are clearly important for defense against infections, but toxic neutrophil mediators can also contribute to the pathogenesis of ALI. Since neutrophils are possible targets for prevention or treatment of lung injury, it is critical to understand the mechanisms that direct neutrophil responses. The objectives of this proposal are to define the molecular pathways that regulate calcium signaling in neutrophils and to determine how these pathways modulate neutrophil activation during ALI.
Proposed specific aims
· Determine the role of calcium sensors STIM1 and STIM2 in neutrophil activation in vitro and during ALI.
· Determine the cooperative interaction between ORAI1 and ORAI2 in neutrophil store-operated
calcium entry (SOCE).
· Determine the mechanism of STIM and ORAI-mediated SOCE and neutrophil activation in human
Potential impact on child health
These studies will elucidate previously unexplored pathways of calcium signaling in neutrophils that may lead to new therapeutic approaches to treat acute lung injury and other inflammatory processes in children.