EpiMIRgen is focussed on understanding the mechanisms of gene expression and gene expression regulation in both the normal healthy brain and in epilepsy. It is particularly focussed on a small group of molecules called microRNAs which can regulate gene expression post-transcriptionally. these small molecules can have profound effects on the gene expression profiles of a cell and influence of the function of the cell in different ways. Little is known about how these molecules interact with other regulators which influence gene expression and whether they "talk to each other" is unclear. EpiMIRgen will try to identify whether this cross-talk exists between microRNAs and a group of proteins which influence gene expression by interacting directly with genes. This interaction may be affected in epilepsy and this will also be investigated.
Epilepsy is a chronic neurological disorder characterised by spontaneous recurrent seizures. It affects about 55 million people worldwide, exacts an enormous toll on human potential and is estimated to cost about Euro 20 billion per year in Europe alone. Additionally, current anti-seizure medications fail about one third of patients so there is a real unmet clinical need to develop novel therapeutics which treat the underlying causes of the disease. There are also a number of comorbidities associated with the disease, for example people who suffer from epilepsy are also more likely to experience anxiety, depression and sudden unexpected death from epilepsy. While some epilepsies are genetic in cause, many are caused by trauma to the brain. These epilepsy-inciting events initiate processes in the brain which then give rise to the spontaneous seizures, these processes include things like neuroinflammation, cell death and reorganisation of surviving neurons. Large scale changes in gene expression and gene expression regulation likely give rise to the common pathological mechanisms of epilepsy development. MicroRNAs are a strong candidate as regulators of this process.
The overall objectives of this project are to explore the role of miRNAs in healthy brain and in epilepsy. We hope to identify the gene networks governed by miRNA and then target these molecules or one/some of its targets to try to block the development of epilepsy in pre-clinical models. We will also assess their biomarker potential as there is also a real need for the development of simple diagnostic tests which can identify patients at risk of developing epilepsy.
Conclusion of the action: Transgenic and reporter mouse models are critical for intensive molecular interrogation of microRNA function in healthy and diseased brain. MicroRNAs have been shown to regulate many cellular processes and neuronal and glial activity but at present there is a dearth of knowledge about the expression profiles of microRNAs in vivo and particularly within complex tissues such as brain. The Ago2-flag-Cre mice generated in this project now allow us to profile miRNA expression within neurons and glia in healthy and diseased brain, specifically changes within these cell types in epilepsy.
Second, the diagnosis of epilepsy and determining whether neonates have experienced a seizure remains fraught with complications requiring EEG. This requires significant resources which are often unavailable in remote regions and in less well developed countries. As such there is a significant need for the development of a molecular, non-invasive biomarker which can accurately predict the development of epilepsy in adults or can identify whether a neonate has experienced a real seizure. MiRNAs possess many physical characteristics which render them excellent potential biomarkers. Human umbilical cord blood plasma could potentially contain molecular signatures useful for the diagnosis of disease or traumatic event such as hypoxic ischemic encephalopathy. For the first time we profiled miRNAs in umbilical cord blood plasma from healthy and diseased babies and found that there are inherent sex differences in cord blood make up as well as editing differences and these may be exploited to stratify babies who have undergone mild, moderate and severe hypoxia and may be useful for the prediction of negative outcome during development.
