Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy

Grants and Contracts Details

Description

Blood-brain barrier dysfunction is recognized as both a cause and consequence of seizures in epilepsy. Two key characteristics of barrier dysfunction in epilepsy include 1) inflammation of the capillary endothelium and 2) barrier leakage, both of which have been linked to seizures. In spite of increasing evidence supporting that glutamate causes blood-brain barrier dysfunction, knowledge of the associated underlying mechanisms remain to be fully defined. Moreover, therapeutic options for restoring barrier function are currently not available. Thus, there is an unmet critical need to determine how glutamate promotes blood-brain barrier inflammation and leakage and to develop targeted strategies to restore barrier function. The consequence of this unmet need is that development of novel treatments to improve seizure control in epilepsy will likely remain a clinical challenge. The long-term goal of the investigator is to contribute toward the development of mechanism-based strategies to repair bloodbrain barrier dysfunction in brain diseases. The overall objective in this application is to establish the efficacy of a mechanism-based intervention to treat blood-brain barrier dysfunction in epilepsy, thereby vertically extending what has been learned under current funding. Based on preliminary data the central hypothesis of this project is that glutamate signaling mediates blood-brain barrier dysfunction and that therapeutic intervention targeting this mechanism will resolve seizure-induced vascular inflammation, repair barrier leakage, and reduce seizure burden. The rationale for the proposed research is that its successful completion will provide a robust framework for the continued development and clinical translation of a novel evidence-based therapeutic intervention to help treat seizures in patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identify signaling steps responsible for seizure-induced inflammation of the blood-brain barrier. 2) Determine the mechanism responsible for glutamate-induced blood-brain barrier leakage, and 3) Develop a therapeutic intervention to reduce seizure burden in a chronic epilepsy model. Under Aim 1, signaling steps that lead to seizure-mediated inflammation of the cerebral vasculature will be determined in capillaries isolated from knockout mouse models and verified in vivo. Under Aim 2, key signaling steps that trigger barrier leakage will be determined in human brain capillaries from seizure-free control individuals and from patients with epilepsy. Under Aim 3, an intervention therapy designed to repair barrier dysfunction will be developed and the therapeutic benefit of this strategy on reducing seizure burden in a rat chronic epilepsy model will be evaluated. The proposed research is innovative, because it represents a substantive departure from the status quo by shifting the focus to molecular targets at the blood-brain barrier to resolve vascular inflammation, restore barrier function, and improve epilepsy symptoms. The proposed research is significant because it holds the promise of a novel therapeutic approach to repair barrier dysfunction that has translational potential for clinical use to advance treatment of patients with epilepsy and other seizure disorders with underlying barrier dysfunction.
StatusActive
Effective start/end date6/15/203/31/26

Funding

  • National Institute of Neurological Disorders & Stroke: $1,210,583.00

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