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GENOMIC AND PROTEOMIC ANALYSIS OF PRION SYNAPTOTOXICITY

Investigators
Harris, David
Institutions
Boston University Medical Campus (BUMC)
Start date
2018
End date
2020
Objective
We have gathered strong evidence that the synaptotoxicity of prions depends on activation of specific signaltransduction pathways that cause changes in protein phosphorylation mediated by key protein kinases, andthat result in downstream alterations in gene transcription. In this project, we propose to use cutting-edgeproteomic techniques and RNA-Seq to analyze global changes in protein phosphorylation and genetranscription in neurons undergoing the earliest detectable changes in synaptic structure and function. We willuse specialized cultures of hippocampal neurons that respond rapidly (within hours) to neurotoxic forms ofPrPSc by retraction of dendritic spines and by alterations in synaptic transmission. We then plan to processthese data using sophisticated bioinformatics pipelines to identify cellular signaling pathways andtranscriptional networks mediating the synaptotoxic effects of PrPSc. We anticipate that the comprehensive,discovery-based approach outlined here will yield important clues to the underlying biology of prion diseases,and will identify a wealth of novel therapeutic targets for ameliorating synaptic degeneration in these disorders.
Funding Source
Nat'l. Inst. of Neurological Disorders and Stroke
Project source
View this project
Project number
1R21NS107755-01A1
Categories
Bacterial Pathogens
Viruses and Prions