title: Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.
abstract: Traumatic brain injury (TBI) is a complex and common problem resulting in the loss of cognitive function. In order to build a comprehensive knowledge base of the proteins that underlie these cognitive deficits, we employed unbiased quantitative mass spectrometry, proteomics, and bioinformatics to identify and quantify dysregulated proteins in the CA3 subregion of the hippocampus in the fluid percussion model of TBI in rats. Using stable isotope 18O-water differential labeling and multidimensional tandem liquid chromatography (LC)-MS/MS with high stringency statistical analyses and filtering, we identified and quantified 1002 common proteins, with 124 increased and 76 decreased. The ingenuity pathway analysis (IPA) bioinformatics tool identified that TBI had profound effects on downregulating global energy metabolism, including glycolysis, the Krebs cycle, and oxidative phosphorylation, as well as cellular structure and function. Widespread upregulation of actin-related cytoskeletal dynamics was also found. IPA indicated a common integrative signaling node, calcineurin B1 (CANB1, CaNBα, or PPP3R1), which was downregulated by TBI. Western blotting confirmed that the calcineurin regulatory subunit, CANB1, and its catalytic binding partner PP2BA, were decreased without changes in other calcineurin subunits. CANB1 plays a critical role in downregulated networks of calcium signaling and homeostasis through calmodulin and calmodulin-dependent kinase II to highly interconnected structural networks dominated by tubulins. This large-scale knowledge base lays the foundation for the identification of novel therapeutic targets for cognitive rescue in TBI.
authors: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1060, USA.
authors: Ping
authors: P
authors: Wu
authors: Yingxin
authors: Y
authors: Zhao
authors: Sigmund J
authors: SJ
authors: Haidacher
authors: Enyin
authors: E
authors: Wang
authors: Margaret O
authors: MO
authors: Parsley
authors: Junling
authors: J
authors: Gao
authors: Rovshan G
authors: RG
authors: Sadygov
authors: Jonathan M
authors: JM
authors: Starkey
authors: Bruce A
authors: BA
authors: Luxon
authors: Heidi
authors: H
authors: Spratt
authors: Douglas S
authors: DS
authors: Dewitt
authors: Donald S
authors: DS
authors: Prough
authors: Larry
authors: L
authors: Denner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019703:Calcineurin / Q000378:metabolism*; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D019703:Calcineurin; C585092:ppp3r1 protein, rat