Our overall objective is to develop a strategy to quantitatively measure protein-protein interactions in signaling networks identified in our phosphoproteome analysis of the Phencyclidine (PCP) Pre-Pulse Inhibition (PPI) model in rats. This research paradigm models a specific cognitive phenotype observed in human schizophrenia. Our previous studies observed perturbation to signaling networks and in this grant period we propose to develop methods to quantitatively measure specific protein-protein interactions of 30 proteins to create a network of proteins altered by PCP/PPI. By examining the interactions of rats treated with PCP to those not treated, we will gain an understanding of how the network is perturbed. We will exploit 15N labeling of rats for quantitative global analysis of the protein complexes comprising part of the signal transduction pathways identified during the previous grant period. Signal transduction is a key elicitor of a diverse array of functions in the brain that impacts different behaviors. The development of technology to analyze 15N labeled rat brain proteins to determine quantitative changes in the network involved in PCP treatment will advance our understanding of molecular changes occurring in this surrogate for the schizophrenia phenotype. In this project, we will develop methods for identifying and quantifying the protein complexes and develop a strategy to perform mixed bottom up and top down of the protein complexes to determine the isoforms and modified of the proteins involved in the complexes. Our hypothesis is that this approach will identify specific molecular processes disrupted by disease. The long term goal is to develop methods and technologies to determine the molecular basis of affective disorders, a health issue for roughly 20 million Americans (5-7% of the population).

Public Health Relevance

Approximately, 20 million Americans are stricken with affective disorders of some type. This research will help establish approaches for examining the molecular processes associated with these disorders. A fundamental understanding of these processes will help the development of therapeutics to alleviate the symptoms associated with affective disorders such as schizophrenia, psychosis, bipolar disorder, and depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH067880-11
Application #
8578055
Study Section
Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
Program Officer
Nadler, Laurie S
Project Start
2003-04-01
Project End
2018-07-31
Budget Start
2013-08-16
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$622,727
Indirect Cost
$294,111
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yonashiro, Ryo; Tahara, Erich B; Bengtson, Mario H et al. (2016) The Rqc2/Tae2 subunit of the ribosome-associated quality control (RQC) complex marks ribosome-stalled nascent polypeptide chains for aggregation. Elife 5:e11794
Borges, Marcia H; Figueiredo, Suely G; Leprevost, Felipe V et al. (2016) Venomous extract protein profile of Brazilian tarantula Grammostola iheringi: searching for potential biotechnological applications. J Proteomics 136:35-47
Chatterjee, Sandip; Stupp, Gregory S; Park, Sung Kyu Robin et al. (2016) A comprehensive and scalable database search system for metaproteomics. BMC Genomics 17:642
McClatchy, D B; Savas, J N; Martínez-Bartolomé, S et al. (2016) Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex. Mol Psychiatry 21:205-15
Savas, Jeffrey N; Park, Sung Kyu; Yates 3rd, John R (2016) Proteomic Analysis of Protein Turnover by Metabolic Whole Rodent Pulse-Chase Isotopic Labeling and Shotgun Mass Spectrometry Analysis. Methods Mol Biol 1410:293-304
Shrestha, Elina; Hussein, Maryem A; Savas, Jeffery N et al. (2016) Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages. J Biol Chem 291:11172-84
Ma, Jiao; Diedrich, Jolene K; Jungreis, Irwin et al. (2016) Improved Identification and Analysis of Small Open Reading Frame Encoded Polypeptides. Anal Chem 88:3967-75
Buffon, Giseli; Blasi, Édina A R; Adamski, Janete M et al. (2016) Physiological and Molecular Alterations Promoted by Schizotetranychus oryzae Mite Infestation in Rice Leaves. J Proteome Res 15:431-46
Lavallée-Adam, Mathieu; Yates 3rd, John R (2016) Using PSEA-Quant for Protein Set Enrichment Analysis of Quantitative Mass Spectrometry-Based Proteomics. Curr Protoc Bioinformatics 53:13.28.1-16
Zhao, Xuan; Hirota, Tsuyoshi; Han, Xuemei et al. (2016) Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation. Cell 165:1644-57

Showing the most recent 10 out of 142 publications