Neutrophil priming following trauma and sepsis is a key event implicated in causing Adult Respiratory Distress Syndrome (ARDS) and Multi-Organ Failure Syndrome (MOSF). Priming of the respiratory burst by cytokines following injury and sepsis results in excessive superoxide production by NADPH oxidase leading to auto-inflammatory tissue damage. Numerous studies have focused on details of how NADPH oxidase produces superoxide. A similar investigation into the mechanisms of priming has been relatively lacking. Our long-term goal is to develop a detailed molecular understanding of this priming phenomenon. Our previous studies and preliminary observations show that different signaling pathways activated by trauma and sepsis converge to phosphorylate two serine residues in a key protein of the NADPH oxidase, p47phox. We propose that through this phosphorylation, p47phox integrates upstream signaling events to control the level of NADPH oxidase activity by regulating protein-protein interactions within neutrophils. In the studies outlined in this proposal the consequences of priming-induced phosphorylation and the identity of proteins associating with NADPH oxidase components following priming will be investigated using neutrophil cell-biological and protein chemistry approaches. The results from these studies may assist in the development of novel therapies aimed at limiting the auto-inflammatory tissue damage patients suffer as a result of sepsis and trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059281-05
Application #
6520006
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1999-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
5
Fiscal Year
2002
Total Cost
$305,491
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Cannell, Ian G; Merrick, Karl A; Morandell, Sandra et al. (2015) A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy. Cancer Cell 28:623-637
Hsu, Albert T; Barrett, Christopher D; DeBusk, George M et al. (2015) Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome. Shock 44:128-36
Morandell, Sandra; Reinhardt, H Christian; Cannell, Ian G et al. (2013) A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Rep 5:868-77
Kang, Seong A; Pacold, Michael E; Cervantes, Christopher L et al. (2013) mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341:1236566
Niedelman, Wendy; Gold, Daniel A; Rosowski, Emily E et al. (2012) The rhoptry proteins ROP18 and ROP5 mediate Toxoplasma gondii evasion of the murine, but not the human, interferon-gamma response. PLoS Pathog 8:e1002784
Cannell, Ian G; Yaffe, Michael B (2011) Salvaging the septic heart through targeting the interleukin-6/p38 mitogen-activated protein kinase signaling network. Crit Care Med 39:1836-7
Smith, Adam; Blois, Joseph; Yuan, Hushan et al. (2009) The antiproliferative cytostatic effects of a self-activating viridin prodrug. Mol Cancer Ther 8:1666-75
Bissonnette, Sarah A; Glazier, Christina M; Stewart, Mary Q et al. (2008) Phosphatidylinositol 3-phosphate-dependent and -independent functions of p40phox in activation of the neutrophil NADPH oxidase. J Biol Chem 283:2108-19
Janes, Kevin A; Albeck, John G; Gaudet, Suzanne et al. (2005) A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science 310:1646-53
Janes, Kevin A; Albeck, John G; Peng, Lili X et al. (2003) A high-throughput quantitative multiplex kinase assay for monitoring information flow in signaling networks: application to sepsis-apoptosis. Mol Cell Proteomics 2:463-73

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