Counter-regulatory Lipid Signals in Lung Disease

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In response to inflammatory stimuli, neutrophils (PMN) remodel cell membranes to generate bioactive lipid-derived signals that serve as intra- or extracellular mediators for the transduction of functional responses. We recently identified polyisoprenyl phosphates (PIPP) as novel, intracellular counter- regulatory signals in PMN. One of these PIPP's, presqualene diphosphate (PSDP), is present in unstimulated cells and, upon cell stimulation, undergoes rapid dephosphorylation with a reciprocal increase in its monophosphate form, PSMP, PSDP, but not PSMP or closely related compounds, inhibits agonist-induced superoxide anion generation and phospholipase D (PLD). Here, the proposed experiments will test the hypothesis that polyisoprenyl phosphates are novel intracellular signals that counteract processes initiated by phosphoinositide signaling. The scientific community has become accustomed to thinking of receptor-ligand interacts as leading to the rapid elaboration of pro-inflammatory intracellular signals, such as phosphoinositol biphosphate (PIP2) and phosphoinositol trisphosphate (PIPS). It is also possible that counter-regulatory lipid signals (e.g., PSDP) are held at a set point in resting cells to provide regulated negative signaling that is rapidly decreased upon cell stimulation. This new paradigm would introduce the notion that inflammatory responses may result, in part, from the release of biochemical "brakes" rather than activation of biochemical "accelerators." To test our hypothesis, we propose three specific aims: 1. determine the key domains and residues in PLD responsible for inhibition by PSDP. 2. determine the relationship between PIPP and phosphoinositide turnover during human PMN stimulation, and 3. elucidate a novel phosphatase responsible for PIPP remodeling during PMN stimulation. From my clinical training as a pulmonologist, I became acutely aware of our incomplete understanding of the pathobiology of pulmonary inflammation. As a new investigator, I am firmly committed to the pursuit of pivotal regulatory mechanisms for pulmonary inflammation. The long-term objectives are two-fold: (i) identify a basis for new interventional strategies that promote resolution of inflammatory responses and (ii) elucidate the role of lipid mediators in respiratory diseases of elderly individuals.