Counter-regulatory Lipid Signals in Lung Disease

中性粒细胞（PMN）对炎症刺激的反应是重塑细胞膜，产生生物活性的脂质衍生信号，作为功能反应转导的细胞内或细胞外介质。 我们最近发现多异戊二烯磷酸（PIPP）是一种新的PMN细胞内反调节信号. 这些PIPP之一，前角鲨烯二磷酸（PSDP），存在于未刺激的细胞中，并且在细胞刺激时，经历快速的去磷酸化，其单磷酸盐形式PSMP、PSDP（但不是PSMP或密切相关的化合物）相反增加，抑制激动剂诱导的超氧阴离子产生和磷脂酶D（PLD）。 在这里，拟议的实验将测试的假设，聚异戊二烯磷酸是新的细胞内信号，抵消磷酸肌醇信号启动的过程。科学界已经习惯于认为受体-配体相互作用会导致促炎细胞内信号的快速产生，例如磷酸肌醇二磷酸（PIP 2）和磷酸肌醇三磷酸（PIPS）。 也有可能是反调节脂质信号（例如，PSDP）在静息细胞中保持在设定点以提供经调节的负信号传导，所述负信号传导在细胞刺激时迅速降低。 这一新的范式将引入这样一种概念，即炎症反应可能部分是由生化“刹车”的释放而不是生化“加速器”的激活引起的。“为了验证我们的假设，我们提出了三个具体目标：1。确定PSDP抑制PLD的关键结构域和残基。2.确定在人PMN刺激期间PIPP和磷酸肌醇周转之间的关系，以及3.阐明了一种新的磷酸酶负责PIPP重塑PMN刺激过程中。从我作为一名肺病学家的临床训练中，我敏锐地意识到我们对肺部炎症的病理生物学的理解不完整。 作为一名新的研究者，我坚定地致力于追求肺部炎症的关键调节机制。 长期目标有两个方面：（i）确定新的干预策略的基础，促进炎症反应的解决和（ii）阐明脂质介质在老年人呼吸系统疾病中的作用。

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.