Defining the role of edited microRNAs in diabetes mediated brain microvasculature alterations

Type-2 diabetes (T2D) mediated hyperglycaemia is associated with an array of negative intracellular events that promote endothelial cells (EC, specialised cells that cover internal linings of the blood vessels) dysfunction and increase permeability in brain microvasculature (consists of ECs and pericytes), leading to hyperglycaemia related neuroinflammation and cognitive decline.

Despite the importance of brain microvasculature EC and pericytes to human brain health, the mechanisms of T2D mediated changes in brain microvasculature ECs and pericytes are poorly defined.

There are several mechanisms that can alter cellular-states and play role in disease, however, in this proposal I will investigate interaction between two key post-transcriptional mechanisms (i) RNA-editing (a mechanism to recode genetic information) and (ii) microRNAs, in brain microvascular dysfunction i.e.

RNA-editing of microRNAs, which can redirect edited-microRNA to a different subset of mRNA targets. The overriding hypothesis is that microvascular compromise plays a key role in cognitive decline in T2D.

Transcriptomic profiles for protein and non-protein coding RNAs will be generated for vascular endothelial cells using T2D mouse model (leptin knockout obese db/db) to predict RNA-edited transcripts.

I hypothesise that these analyses will reveal dysregulated/RNA-edited transcripts related to angiogenesis, vasoconstriction/vasodilation and platelet-activation pathways, informing new avenues for research and novel therapeutic-insights.