Yale/NIDA Neuroproteomics Center

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

Overall Summary We propose to continuously improve the Yale/NIDA Neuroproteomics Center that brings exceptionally strong Yale programs in proteomics and signal transduction in the brain together with neuroscientists from 9 other universities across the U.S. to maintain a virtual national resource that will collaborate to identify adaptive changes in protein signaling that occur in response to substances of abuse. Twenty-six faculty with established records of highly innovative research into the molecular actions of psychoactive addictive drugs, as well as of other basic aspects of neurobiology, will work together in a unique synergy with the Yale Keck Laboratory to support the Center, whose theme is “Proteomics of Altered Signaling in Addiction”. The Center will use cutting edge proteomic technologies to analyze neuronal signal transduction mechanisms and the adaptive changes in these processes that occur in response to drugs of abuse. With Co-Directors Angus Nairn (Psychiatry) and Ken Williams (Mol. Biophys. & Biochem.) in the Administrative Core, the Center includes Discovery Proteomics (DPC) and Targeted Proteomics (TPC) Cores. Biophysical technologies from the DPC extend protein profiling analyses into the functional domain while phosphoinositide and lipid dynamics analyses from the DPC leverage proteome analyses to provide an increasingly systems level view. A Biostatistics and Bioinformatics Core that includes high performance computing and the Bioinformatics Support Program in the Yale Medical Library provides essential support that leverages the value of the proteomic technology cores. A Pilot Research Projects Core is vital for cultivating strong mentoring relationships and training the next generation of substance abuse researchers. Technology pilot grants continuously drive innovation within the Center. Behavioral adaptations that accompany drug addiction are believed to result from short and long-term adaptive changes in brain reward centers. Thus, exposure to drugs of abuse regulates intracellular signaling processes that alter gene expression, protein translation, and protein post-translational modifications (PTMs). Repeated exposure to drugs of abuse leads to stable alterations in these signaling systems that are critical for the changes in brain chemistry and structure of the addicted brain. Center Investigators will study the actions of cannabis, cocaine, nicotine, and opioids on these intracellular signaling pathways in brain reward areas and work with Center Cores to enable proteomic analysis of the single types of neurons that define the circuits that underlie the actions and addictive properties of these drugs of abuse. Data-independent and targeted mass spectrometry approaches, together with next generation proximity labeling methods, will be used to analyze the impact of addictive drugs on the neuroproteome and its PTMs in a cell type- and subcellular-specific manner. Together the Center Cores will develop novel methods for deep integration of genomic, transcriptomic, and proteomic data with brain region, cell type-specificity.