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

基本信息

批准号：
9976832
负责人：
Bjoern Bauer
金额：
$ 60.88万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9976832
关键词：
Agonist Arachidonate 5-Lipoxygenase Attenuated Automobile Driving Blood - brain barrier anatomy Blood capillaries Brain Diseases Cell Adhesion Molecules Characteristics Chronic Clinical Data Data Reporting Development Disease Endothelium Epilepsy Extracellular Matrix Proteins Extravasation FPR2 gene Feedback Functional disorder Funding Glutamates Goals Human Inflammation Intervention Knockout Mice Knowledge LOX gene Lead Leukocytes Leukotrienes Link Matrix Metalloproteinases Mediating Mission Modeling Molecular Target Mus National Institute of Neurological Disorders and Stroke Neurons Neurotransmitters 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 base cerebral capillary clinical translation cyclooxygenase 2 evidence base expectation glutamatergic signaling improved in vivo individual patient innovation lipoxin A4 mouse model nervous system disorder neuroinflammation neurovascular new therapeutic target novel novel therapeutic intervention novel therapeutics repaired therapy design vascular inflammation

项目摘要

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既是癫痫发作的原因又是结果。两个键癫痫中屏障功能障碍的特征包括1）神经血管炎症和2）屏障泄漏，两者都与癫痫发作有关。尽管有越来越多支持谷氨酸引起的证据血脑屏障功能障碍，相关基本机制的知识仍有待完全定义。此外，目前尚无用于恢复障碍功能的治疗选择。因此，有一个未满足的确定谷氨酸如何促进血脑屏障炎症和泄漏并发展的迫切需要恢复障碍功能的有针对性策略。这种未满足的需求的结果是新颖的发展改善癫痫中癫痫发作控制的治疗可能仍然是临床挑战。长期目标研究者将有助于制定基于机制的策略来修复血脑屏障脑疾病功能障碍。该应用程序的总体目的是确定机制的功效 - 基于治疗癫痫中血脑屏障功能障碍的干预措施，从而垂直扩展了根据目前的资金学习。基于初步数据，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和针对此机制的治疗干预措施将解决癫痫发作引起的神经血管炎症，修复屏障泄漏并减轻癫痫发作负担。这拟议研究的理由是，其成功完成将为该研究提供一个强大的框架持续开发和新型循证治疗干预措施的临床翻译，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）确定信号传导步骤导致癫痫发作引起的血脑屏障炎症。 2）确定负责人血脑屏障的毛细血管泄漏的机制，3）发展治疗干预以减轻慢性癫痫模型中的癫痫发作负担。在AIM 1下，发出信号的步骤导致癫痫发作介导的神经炎症将在从敲除小鼠模型中分离出的毛细血管中确定在体内验证。在AIM 2下，将确定在人脑中触发屏障泄漏的关键信号步骤来自无癫痫发作的个体和癫痫患者的毛细血管。在AIM 3下，干预旨在修复障碍功能障碍的治疗将开发出来，并且此策略的治疗益处减少癫痫发作负担将在大鼠慢性癫痫模型中评估。拟议的研究是创新的，因为它通过将焦点转移到分子靶标，代表了与现状的实质性不同解决神经血管炎症，恢复障碍功能并改善癫痫的血脑屏障症状。拟议的研究很重要，因为它具有新型治疗方法的希望修复具有临床用途的转化潜力以促进患者的治疗癫痫病和其他癫痫发作障碍，具有潜在的屏障功能障碍。