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

血脑屏障功能障碍被认为是癫痫发作的原因和后果。两把钥匙 癫痫的屏障功能障碍的特征包括1)神经血管炎症和2)屏障渗漏， 这两种疾病都与癫痫有关。尽管越来越多的证据支持谷氨酸导致 血脑屏障功能障碍，相关潜在机制的知识仍有待充分界定。 此外，目前还没有恢复屏障功能的治疗选择。因此，有一个未得到满足的 迫切需要确定谷氨酸如何促进血脑屏障炎症和渗漏 有针对性的恢复屏障功能的策略。这种未得到满足需求的结果是小说的发展 改善癫痫发作控制的治疗可能仍然是一个临床挑战。中国的长期目标是 研究人员将为开发基于机制的修复血脑屏障的策略做出贡献 脑部疾病中的功能障碍。本申请的总体目标是建立一种机制的效力- 基于干预治疗癫痫患者的血脑屏障功能障碍，从而垂直扩展 在现有资金下学到的。根据初步数据，该项目的中心假设是谷氨酸 信号转导血脑屏障功能障碍及针对该机制的治疗干预 会化解癫痫引起的神经血管炎症，修复屏障渗漏，减轻癫痫负担。这个 拟议研究的理由是，它的成功完成将为 一种新的循证治疗干预措施的持续开发和临床翻译 癫痫患者的癫痫发作。这一假设将通过追求三个具体目标来检验：1)确定 导致癫痫发作引起的血脑屏障炎症的信号步骤。2)确定 人类血脑屏障毛细血管渗漏的机制，以及3)开发一种治疗方法 干预以减轻慢性癫痫模型中的癫痫发作负担。在目标1下，发出信号步骤导致 癫痫介导的神经炎症将在从基因敲除小鼠模型和 在体内进行了验证。根据目标2，触发屏障渗漏的关键信号步骤将在人脑中确定 来自无癫痫对照个体和癫痫患者的毛细血管。在目标3下，干预 旨在修复屏障功能障碍的疗法将被开发出来，这一策略的治疗益处将在 减轻癫痫发作负担将在大鼠慢性癫痫模型中进行评估。这项拟议的研究具有创新性， 因为它代表了对现状的实质性偏离，将焦点转移到分子靶标上 血脑屏障可消解神经血管炎症，恢复屏障功能，改善癫痫 症状。这项拟议的研究意义重大，因为它蕴含着一种新的治疗方法的前景。 修复具有翻译潜力的屏障功能障碍，以促进患者的治疗 癫痫和其他伴有潜在屏障功能障碍的癫痫。

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) neurovascular inflammation 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 blood-brain 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 neurovascular 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 capillary leakage at the human blood-brain barrier, 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 neuroinflammation 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 will be evaluated in a rat chronic epilepsy model. 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 neurovascular 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.