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

解决癫痫神经血管炎症和修复血脑屏障功能障碍的新治疗策略

• 批准号: 10380864
• 负责人: Bjoern Bauer
• 金额: $ 56.17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380864
• 关键词: Agonist; Arachidonate 5-Lipoxygenase; Attenuated; Automobile Driving; Blood - brain barrier anatomy; Blood brain barrier dysfunction; Blood capillaries; Brain Diseases; Cell Adhesion Molecules; Characteristics; Chronic; Clinical; Combined Modality Therapy; Data; Data Reporting; Development; Disease; Endothelium; Epilepsy; Extracellular Matrix Proteins; Extravasation; FPR2 gene; Feedback; Functional disorder; Funding; Glutamates; Goals; Human; Individual; Inflammation; Intervention; Knockout Mice; Knowledge; LOX gene; Lead; Learning; Leukocytes; Leukotrienes; Link; Lipoxygenase; Matrix Metalloproteinases; Mediating; Mission; Modeling; Molecular Target; Mus; National Institute of Neurological Disorders and Stroke; Neurons; PTGS2 gene; Pathway interactions; Patients; Prostaglandins; Proteins; Public Health; Publishing; Rattus; Research; Research Personnel; Seizures; Signal Transduction; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; United States National Institutes of Health; cerebral capillary; clinical translation; cyclooxygenase 2; evidence base; expectation; glutamatergic signaling; improved; in vivo; innovation; mouse model; nervous system disorder; neuroinflammation; neurotransmitter release; neurovascular; new therapeutic target; novel; novel therapeutic intervention; repaired; therapy design; translational potential; vascular inflammation

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.

血脑屏障功能障碍被认为是癫痫发作的原因和后果。两键 癫痫屏障功能障碍的特征包括 1) 神经血管炎症和 2) 屏障渗漏， 两者都与癫痫发作有关。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完全确定。 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并开发 恢复屏障功能的针对性策略。这种未满足的需求的后果是小说的开发 改善癫痫发作控制的治疗可能仍然是一个临床挑战。该组织的长期目标 研究者致力于开发基于机制的修复血脑屏障的策略 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有效性- 以治疗癫痫血脑屏障功能障碍为基础的干预措施，从而垂直扩展已取得的成果 在当前资金下学习。根据初步数据，该项目的中心假设是谷氨酸 信号传导介导血脑屏障功能障碍，并且针对该机制的治疗干预 将解决癫痫引起的神经血管炎症，修复屏障渗漏，并减轻癫痫负担。这 拟议研究的理由是，其成功完成将为 持续开发和临床转化新型循证治疗干预措施，以帮助治疗 癫痫患者的癫痫发作。该假设将通过追求三个具体目标来检验：1）确定 负责癫痫引起的血脑屏障炎症的信号传导步骤。 2）确定 负责人体血脑屏障毛细血管渗漏的机制，以及 3) 开发治疗方法 干预以减轻慢性癫痫模型的癫痫发作负担。在目标 1 下，发出信号的步骤导致 癫痫介导的神经炎症将在从基因敲除小鼠模型中分离的毛细血管中确定 体内验证。在目标 2 下，触发屏障渗漏的关键信号步骤将在人脑中确定 来自无癫痫发作对照个体和癫痫患者的毛细血管。在目标 3 下，干预 将开发旨在修复屏障功能障碍的疗法，并且该策略的治疗益处 将在大鼠慢性癫痫模型中评估减少癫痫发作负担。所提出的研究具有创新性， 因为它代表着对现状的实质性背离，将重点转移到分子目标上 血脑屏障，解决神经血管炎症，恢复屏障功能，改善癫痫 症状。拟议的研究意义重大，因为它有望提供一种新颖的治疗方法 修复屏障功能障碍，具有临床应用转化潜力，以促进患有以下疾病的患者的治疗 癫痫和其他具有潜在屏障功能障碍的癫痫疾病。