Neutrophil transfusion has been commonly utilized as a therapeutic approach for the treatment of lifethreatening bacterial and fungal infections in severe neutropenic patients. However, its clinical outcome is often hampered by short ex vivo shelf life and rapid in vivo death, inefficiency of recruitment to sites of inflammation, and poor pathogen killing capability of transplanted neutrophils. The ultimate goal ofthe proposed research is to identify and characterize cellular and molecular events that can improve neutrophil performance during transfusion. We are particularly interested in a signal pathway mediated by inositol phospholipid Ptdlns(3,4,5)P3. Recently, we have shown that the responsiveness of neutrophil to chemoattractant stimulation is much enhanced in PTEN knockout mice in which the Ptdlns(3,4,5)P3 signaling is hyperactivated. The recruitment of neutrophils to the inflamed peritoneal cavity was significantly elevated in these mice. In addition, augmenting Ptdlns(3,4,5)P3 signal via depleting PTEN prevents neutrophil spontaneous death. Moreover, we recently reported that neutrophil functions, such as chemotaxis, oxidative burst, recruitment to the sites of inflammation, were also augmented in lnsP3KB""""""""'"""""""" neutrophils, in which the Ptdlns(3,4,5)P3 signal is elevated due to the depletion of lns(1,3,4,5)P4, an intracellular inhibitory modulator of Ptdlns(3,4,5)P3 signaling. These intriguing results led us to hypothesize that the efficacy of neutrophil transfusion can be improved by augmenting Ptdlns(3,4,5)P3 signaling in neutrophils. In this proposed study, we will use a mouse neutrophil transfusion model to test this hypothesis. First, we will investigate whether augmenting Ptdlns(3,4,5)P3 signaling can enhance the survival of transfused neutrophils (Aim l-Experiment A and B). In addition, we will examine whether the recruitment of transfused neutrophils to the sites of inflammation is enhanced by elevating Ptdlns(3,4,5)P3 signaling (Aim I- Experiment C and D). Finally, since the performance of transfused neutrophils is eventually reflected by the recipients'capability of clearing invading pathogens, we will determine whether augmenting Ptdlns(3,4,5)P3 signaling in transfused neutrophils can ultimately enhance the inflammatory response and bacteria killing capability ofthe recipient mice (Aim II). Experiments proposed in this study will provide insight into the mechanism of action of Ptdlns(3,4,5)P3 pathway in elevating the function of transfused neutrophils, with the ultimate goal of solidifying Ptdlns(3,4,5)P3 and related pathways as novel therapeutic targets for improving the performance of neutrophils in neutrophil transfusion. The ultimate goal of this research is in accordance with the oeneral theme of current PPG which is """"""""to understand how transfused blood cells function at a molecular level""""""""

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National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Children's Hospital Boston
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