An Investigation of the Role of Insulin Deficiency and Loss of PI3K-Akt Signaling Downstream Regulators GSK3β -CREB Signaling in the Pathogenesis of the Diabetic Brain

Our lab has developed a robust streptozotocin-induced murine model with changes analogous to those observed in human diabetic brain, and our lab has shown that replacement of insulin in the brain via intranasal delivery prevents diabetes mellitus (DM) mediated neurodegeneration. Insulin is speculated to act through activation of PI3K-Akt signaling. We hypothesized that the neurodegenerative changes and cognitive impairments observed in the chronic type 1 DM brain occur through impaired insulin-mediated phosphorylation of CREB/GSK3β, critical neuronal signals downstream of PI3K-Akt pathway and direct support of these proteins will prevent these neurodegenerative changes. A transgenic murine model with downregulation of CREB in the forebrain was used to complement interventions to attempt to rescue the chronic type 1 DM brain. Intranasal TDZD-8 was used to inhibit GSK3β in wild type mice. Our results are consistent with the hypothesis that CREB is essential for brain insulin signaling but that GSK3β might not be directly involved in this pathway.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Neuroscience

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2014

Author dc:creator

• ALRAZI, TAZRINA

Advisor dc:contributor.advisor

• FRENCH, ROBERT

• Neuroscience

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/24919

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/1621