Following activation of inflammatory cells, enhanced bulk transbilayer movement of plasma membrane phospholipids (flip-flop) of scramblase results in profound biological consequences. The appearance of phosphatidylserine in the plasma membrane outer leaflet results in the marked enhancement of coagulation, either appropriate as in hemostasis, or inappropriate as in acute lung injury. Similarly, the appearance of phosphatidylserine markedly enhances complement activation and serves as a signal for the recognition and uptake of apoptotic cells by phagocytes. Furthermore, scramblase activation will result in either release (from the synthesizing cell) or uptake (into target cells) of mediator phospholipids (platelet activating factor (PAF), lysophospholipids, and oxidized phospholipids) or their precursors (delivery of arachidonate to secreted PLA2). Depending on cell type, stimulus, and isoform of the scramblase, it is hypothesized that at least four mechanisms are involved in regulating scramblase activity: a) phosphorylation of scramblase by PKC (e.g. fMLP-stimulated neutrophils or Jurkat cell apoptosis), b) elevation of intracellular calcium in the absence of phosphorylation (e.g. thrombin-stimulated platelets), c) translocation to and from the membrane (fMLP-stimulated neutrophil) and d) cytokine-mediated up-regulation of scramblase expression (interferon alpha treated Raji cells).
The aims of this project are to define the regulation of scramblase by phosphorylation and determine the mechanism(s) by which scramblase enhances transbilayer movement of membrane phospholipids. Integrated biochemical, structural and genetic approaches are described in which the scramblase phosphorylation activity, be identified and the effect of phosphorylation on scramblase activity, particularly with regard to calcium requirement, defined. Similarly, these same integrated approaches will be used to define the mechanism by which scramblase mediates the transbilayer movement of phospholipids, hypothesized to require either self-association or association with other proteins.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Zemski Berry, Karin A; Murphy, Robert C; Kosmider, Beata et al. (2017) Lipidomic characterization and localization of phospholipids in the human lung. J Lipid Res 58:926-933
Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306
Gibbings, Sophie L; Thomas, Stacey M; Atif, Shaikh M et al. (2017) Three Unique Interstitial Macrophages in the Murine Lung at Steady State. Am J Respir Cell Mol Biol 57:66-76
Jayaraja, Sabarirajan; Dakhama, Azzeddine; Yun, Bogeon et al. (2016) Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection. BMC Immunol 17:27
Kandasamy, Pitchaimani; Numata, Mari; Berry, Karin Zemski et al. (2016) Structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor 2 and 4 signaling. J Lipid Res 57:993-1005
Zemski Berry, Karin A; Murphy, Robert C (2016) Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages. Chem Res Toxicol 29:1355-64
Frasch, S Courtney; McNamee, Eóin N; Kominsky, Douglas et al. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-?. J Immunol 197:1425-34
Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:
Yun, Bogeon; Lee, HeeJung; Jayaraja, Sabarirajan et al. (2016) Prostaglandins from Cytosolic Phospholipase A2?/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages. J Biol Chem 291:7070-86
Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni et al. (2016) Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes. Am J Respir Crit Care Med 193:614-26

Showing the most recent 10 out of 268 publications