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).
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.
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