Investigation of the disruption of miRNA-137 and its effects on the Nrg/ErbB4 pathway in schizophrenia 公开

Gu, George (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/pn89d6613?locale=zh
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Abstract

Schizophrenia is a mental disorder that affects over 51 million people worldwide. The disease is characterized by delusions and has a molecular mechanism that is poorly understood. The etiology of schizophrenia has both a genetic and environmental background that could be attributed to interferences of certain protein ligands and different signaling pathway. Neuregulin-1 (Nrg1) is an epidermal growth factor that is implicated as a key candidate in schizophrenia. Research has shown that the dysregulation of Nrg1 interaction with ErbB4, a receptor tyrosine kinase, results in neurodevelopmental defects as well as impaired synaptic connectivity in the hippocampus. Findings also show the significant roles that miRNAs play in manipulating the expression of target genes as well as their importance in proper developmental processes in neurons. To date, there has been some data showing the regulatory effect of a specific miRNA-137 on protein expression and dendritic morphology under the Nrg/ErbB4 pathway, but the mechanism by which this happens is still unclear. We designed an experiment utilizing western blots to look at the expression levels of GSK3β under the disruption of miRNA-137. We hypothesize that miRNA-137 overexpression will cause a disruption in GSK3β protein expression levels through a direct mechanism. In addition, we also used immunofluorescence to assess the effect of miRNA-137 overexpression on dendritic morphology. We believe that overexpression of miRNA-137 would disrupt neuregulin signaling and ultimately inhibit dendritic morphology. Our third aim incorporates a PLA assay to look at the effect of neuregulin stimulation on MAP2 protein synthesis. We hypothesize MAP2 protein synthesis to increase under the influence of neuregulin. Results show that miRNA-137 overexpression decreases the phospho and total protein expression levels of GSK3β. A similar trend was also observed in morphology, in that miR-137 overexpression decreased dendritic arborization in nucleofected neurons (nonsignificant). Neuregulin also stimulated the synthesis of MAP2 proteins in the dendritic region, although more trials are required to replicate these results. Taken together, this study not only provides support that miR-137 is an important modulator of specific signaling pathways implicated in schizophrenia, but also paves the way for a novel approaches toward understanding the etiology of this disease.

Table of Contents

Table of Contents

Introduction……………………………………………………………………………………………………………………………...1

Materials and Methods…………………………………………………………………………………………………………...10

Results……………………………………………………………………………………………………………………………………..15

Discussion………………………………………………………………………………………………………………………………..20

Figures……………………………………………………………………………………………………………………………………..25

References……………………………………………………………………………………………………………………………....32

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