Molecular mechanisms of blood-brain barrier dysfunction and repair in epilepsy
Dr C Ruedell Reschke
Prof D Henshall
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
Epilepsy is a common, chronic neurological disorder characterized by recurrent, unprovoked seizures. Current treatments fail at least one third of patients and we have no diseasemodifying therapies. Thus, there is a critical need for new ideas about patho-mechanisms of epilepsy. The blood-brain barrier (BBB) is a critical structure comprising specialized endothelial cells with tight junctions that physically and chemically separates brain tissue from circulating factors in the blood. Acute injuries to the brain and certain chronic neurological diseases are associated with BBB impairment which allows passage of molecules and cells normally excluded into brain tissue. This is thought to cause inflammation and promote neuronal dysfunction. There is growing evidence that epilepsy is associated with BBB dysfunction. Moreover, when seizures occur they may directly open the BBB and further promote molecular changes that contribute to an enduring state of hyper-excitability.
Several key questions remain unanswered which form the basis for the hypothesis to be tested in this PhD project. What are the molecular changes within the BBB that contribute to barrier breakdown? What is the mechanism initiating and maintaining these changes? What size of molecular pore is required to provoke or maintain epilepsy? How long must barrier breakdown persist in order to be epileptogenic? Can epilepsy be resolved by repairing the BBB? If so, how and is there a time limit on when this is possible?
This PhD research project will involve a multi-disciplinary approach comprising neuroscience, genetics, RNA and protein chemistry, microscopy and neuropharmacology to explore the molecular mechanisms of BBB dysfunction and its repair in epilepsy. The project will feature a strong imaging component, including use of pre-clinical models of epilepsy and two-photon microscopy and magnetic resonance imaging (MRI) to study blood brain barrier function in the living brain. A translational research element will involve opportunities to analyze human brain samples from patients with epilepsy and feature the design and delivery of gene therapy and oligonucleotide-based experimental treatments to restore BBB integrity. The researcher will work with a highly dynamic team of neuroscientists based at the recently launched FutureNeuro Research Centre at RCSI as well as molecular biologists, clinicians and bioinformaticists and our broader network of scientific and clinical collaborators.
In summary, this project will provide a neuroscience-focused researcher with a comprehensive, diverse and cutting-edge training experience that will uncover novel molecular mechanisms and treatments for BBB dysfunction in epilepsy.