Combinatorial Biosignatures of Network Dysfunction to Predict Posttraumatic Epilepsy: Clinical Translation from a Robust Mouse Model
Abstract
Brain trauma is a major cause of death and disability that affects people of all ages, and the first cause of death among young adults. One of the major and disabling neurological sequelae of brain trauma is the development of epilepsy. There is a long period of time between the occurrence of the trauma and the development of epilepsy. This would be the perfect time for therapeutic interventions aimed at preventing or arresting the disease. However, there is no easy way to predict which individuals among trauma survivors will develop epilepsy and when this will happen. Therefore, there is urgent need for biological markers that could be used to identify the patients at risk, thereby allowing to design affordable clinical studies, thus possibly developing better prevention and cure for post-traumatic epileptic patients. In this project, we plan to investigate whether the changes in the brain involved in the mechanisms leading to epilepsy can be mirrored by a combination of specific non-invasive parameters. Using in vivo imaging combined with electroencephalography and measurements of selected blood molecules, we aim at identifying key measures predictive of epilepsy development. To accomplish this goal, we will use our in vivo mouse model of post-traumatic epilepsy. In this model, ~50% of trauma-exposed mice develop epilepsy, thus providing an optimal platform for identifying the combination of measures and factors associated with the development of epilepsy. Our last aim has an added human translational component, where key measures/key biosignatures identified in the preclinical model will be subjected to preliminary clinical verification using archived serum samples from traumatic brain injured patients with/without epilepsy collected within two cohorts of patients at Cambridge University. We expect to: (1) identify in the experimental model a palette of minimally invasive biomarkers to predict development of epilepsy after traumatic brain injury and monitor disease progression and (2) understand which kind of patient is more likely to develop epilepsy after trauma, thus providing clinical relevant prognostic tools that could greatly facilitate the clinical development of preventive therapies. The identification and preliminary clinical verification of mechanism-driven biomarkers of post-traumatic epilepsy will provide direct positive impact and benefit to the civilian, military, and Veteran communities. Our project synergizes multi-institutional and interdisciplinary competences and skills between teams in Italy, United Kingdom, and USA, which have a long-dated expertise and track-record in brain trauma, epilepsy, and biomarker discovery, making them highly likely to successfully accomplish the project’s goals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910733
Entities
People
- Elisa Zanier
Organizations
- Mario Negri Institute for Pharmacological Research
- United States Army