This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neuroinflammation is an important factor in the pathogenesis of a number of human neurodegenerative disorders resulting in neuronal cell loss and dementia. The objectives of this proposal are to determine specifically the contribution that phospholipases A2 (PLA2)- and phospholipases C (PLC)-mediated signal transduction have in the progression of cell loss in a rat model of neuroinflammation. It is known that the activation of these enzymes participate in the neuroinflammatory cascade by releasing second messenger molecules that influence ionic channels, glutamate release, and that can be converted to biologically active eicosanoids. Induction of these cascades also disrupts brain metabolism and increases the expression of enzymes found in the inflammatory cascades. However, little is known concerning the contribution that these signaling pathways have in the sequel of events that result in cell death during neuroinflammation. The goals of this project are to test our central hypothesis that phospholipase activation is an initial convergence point of the neuroinflammatory reaction and is essential for the progression of injury that results in neural cell death. This will be accomplished by pursuing the following Specific Aims: 1) Identify brain inflammatory signaling pathways in vivo, 2) Determine the contribution of PLC/PI3 kinase activation in TNF-a release and glial activation, and 3) Evaluate strategies for intervention by disrupting PLA2 expression in vivo. To test our hypothesis, we will use steady-state radiotracer kinetic analysis, biochemical assays, gene expression analysis, immuno histochemistry, behavioral studies, and enzyme inhibiting strategies. During these studies we will determine the contribution that both PLA2 and PLC and the subsequent turnover of membrane phospholipids have in initiating cascades that result in injury associated with neuroinflammation, determine the contribution that receptor/G-protein coupled activation of the PLC/PI3 kinase pathway has in altering lipid-mediated cascades that result in the induction of inflammatory cascades, and determine specifically the contribution that type IVA cytosolic PLA2 has in the progression of inflammatory cell death by inhibiting its activity and expression using inhibitor cocktails and siRNA technology. These studies will provide the information needed to evaluate the contribution that PLA2- and PLC-mediated signaling has in the temporal progression of cell loss in neuroinflammation.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017699-10
Application #
8360141
Study Section
Special Emphasis Panel (ZRR1-RI-5 (01))
Project Start
2011-06-01
Project End
2012-07-14
Budget Start
2011-06-01
Budget End
2012-07-14
Support Year
10
Fiscal Year
2011
Total Cost
$248,721
Indirect Cost
Name
University of North Dakota
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Sukumaran, Pramod; Schaar, Anne; Sun, Yuyang et al. (2016) Functional role of TRP channels in modulating ER stress and Autophagy. Cell Calcium 60:123-32
Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney et al. (2016) The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice. Neurobiol Aging 40:22-40
Liu, Qing Yan; Koukiekolo, Roger; Zhang, Dong Ling et al. (2016) Molecular events linking cholesterol to Alzheimer's disease and inclusion body myositis in a rabbit model. Am J Neurodegener Dis 5:74-84
Moritz, Amy E; Rastedt, Danielle E; Stanislowski, Daniel J et al. (2015) Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics. J Biol Chem 290:29095-105
Zhou, Xikun; Ye, Yan; Sun, Yuyang et al. (2015) Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase C? Signaling. Mol Cell Biol 35:2729-39
Puig, Kendra L; Lutz, Brianna M; Urquhart, Siri A et al. (2015) Overexpression of mutant amyloid-? protein precursor and presenilin 1 modulates enteric nervous system. J Alzheimers Dis 44:1263-78
Zhang, Shuang; Yu, Min; Guo, Qiang et al. (2015) Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. Sci Rep 5:15859
Rojanathammanee, Lalida; Floden, Angela M; Manocha, Gunjan D et al. (2015) Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition. J Neuroinflammation 12:42
Wallert, Mark A; Hammes, Daniel; Nguyen, Tony et al. (2015) RhoA Kinase (Rock) and p90 Ribosomal S6 Kinase (p90Rsk) phosphorylation of the sodium hydrogen exchanger (NHE1) is required for lysophosphatidic acid-induced transport, cytoskeletal organization and migration. Cell Signal 27:498-509
Cain, Jacob T; Berosik, Matthew A; Snyder, Stephanie D et al. (2014) Shifts in the vascular endothelial growth factor isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain. Dev Neurobiol 74:63-81

Showing the most recent 10 out of 175 publications