Blood-brain barrier function in epilepsy: new targets for therapy

癫痫中的血脑屏障功能：治疗的新目标

基本信息

批准号：
8887163
负责人：
Bjoern Bauer
金额：
$ 32.67万
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887163
关键词：
Antiepileptic Agents Blood Blood - brain barrier anatomy Blood capillaries Brain Chronic Clinic Clinical Data Development Disease Drug resistance Epilepsy Extravasation Frequencies Functional disorder Glutamates Goals Health Knowledge LOX gene Lead Leukotrienes Link Maps Matrix Metalloproteinases Metalloproteases Mining Mission Modeling Molecular Monitor National Institute of Neurological Disorders and Stroke Outcome PTGS2 gene Pathology Pathway interactions Patients Pharmacotherapy Proteins Public Health Rattus Research Resistance Seizures Severities Signal Pathway Signaling Protein Testing Therapeutic Tight Junctions Translating United States National Institutes of Health Up-Regulation arm capillary design glutamatergic signaling improved inhibitor/antagonist innovation nervous system disorder novel strategies prevent protein expression repaired sis Genes targeted treatment therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): There is a lack in understanding the mechanism responsible for blood-brain barrier dysfunction in epilepsy. This is a significant clinical challene since it prevents development of a therapy to overcome antiepileptic drug (AED) resistance and reduce seizure burden. Our long-term goal is to elucidate the mechanisms that regulate blood-brain barrier function, which may lead to new strategies to treat epilepsy and other neuro- logical diseases. The objectives in this application are to identify the mechanism(s) by which seizures trig- ger barrier dysfunction, and map key signaling proteins that can potentially serve as targets to repair the blood-brain barrier in epilepsy. Accomplishing these objectives is expected to increase AED brain uptake and reduce seizure burden. Our central hypothesis is that 1) glutamate activates the two-arm LOX/COX pathway, thereby decreasing expression and activity of influx transporters, and upregulating expression and activity of efflux transporters through the COX arm, that 2) glutamate triggers development of barrier leakage through the LOX arm; and that 3) inhibiting cPLA2 to block both arms of the LOX/COX pathway reverses barrier dysfunction and thereby reduces seizure burden. The rationale for this research is that identifying the mechanism(s) responsible for changes in transporter expression and activity, and barrier leakage will potentially provide new targets to improve epilepsy treatment and better control seizures. To accomplish the objectives of this application, our hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of seizure-induced changes of transporter expression and activity; 2) Deter- mine the mechanism of seizure-induced blood-brain barrier leakage; and 3) Develop a therapeutic strategy to reduce seizures in chronic epileptic rats. In Aim 1, we will block cPLA2 and COX-2 to reverse seizure-induced changes in transporter expression and activity. We will monitor influx and efflux transporter expression and activity, and determine AED brain uptake. In Aim 2, we will inhibit cPLA2 and 5-LOX to map the signaling pathway causing seizure-induced barrier leakage. We will determine expression of tight junction proteins and matrix metalloproteases, and assess barrier leakage. In Aim 3, we will evaluate the therapeutic benefit of cPLA2 inhibition on seizure burden in a rat chronic epilepsy model by determining influx and efflux transporter expression and activity, assessing barrier leakage, and monitoring seizure frequency, duration and severity. The proposed research is innovative because it is focused on a new, integrated strategy that considers blood-brain barrier transporters, as well as barrier leakage, and it is designed specifically to repair te barrier to overcome AED resistance and reduce seizures. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with resistant epilepsy. The proposed research is translational because cPLA2 inhibitors are under development, and our strategy has potential to be translated into the clinic.

描述（由申请人提供）：缺乏理解导致癫痫中血脑屏障功能障碍的机制。这是一个重要的临床挑战，因为它可以防止开发克服抗胃药（AED）耐药性并减轻癫痫发作负担的疗法。我们的长期目标是阐明调节血脑屏障功能的机制，这可能导致治疗癫痫病和其他神经疾病的新策略。本应用程序中的目标是确定癫痫发作障碍功能障碍的机制，并绘制有可能用作修复癫痫中血脑屏障的靶标的密钥信号蛋白。实现这些目标有望增加AED大脑的吸收并减轻癫痫发作负担。我们的中心假设是1）谷氨酸激活两臂LOX/COX途径，从而降低涌入转运蛋白的表达和活性，并上调通过Cox臂的外排转运蛋白的表达和活性。 3）抑制CPLA2阻止LOX/COX途径的两个臂逆转障碍障碍，从而减轻了癫痫发作负担。这项研究的理由是，确定负责转运蛋白表达和活性变化的机制，屏障泄漏将有可能提供新的靶标，以改善癫痫治疗和更好的控制癫痫发作。为了实现此应用程序的目标，我们的假设将通过追求三个具体目的来检验：1）确定癫痫发作诱导的转运蛋白表达和活性变化的机制； 2）确定癫痫发作引起的血脑屏障泄漏的机制； 3）制定一种治疗策略，以减少慢性癫痫大鼠的癫痫发作。在AIM 1中，我们将阻止CPLA2和COX-2逆转癫痫发作诱导的转运蛋白表达和活性的变化。我们将监测涌入和外排运输蛋白的表达和活性，并确定AED脑的吸收。在AIM 2中，我们将抑制CPLA2和5-LOX绘制引起癫痫发作诱导的屏障泄漏的信号通路。我们将确定紧密连接蛋白和基质金属蛋白酶的表达，并评估屏障泄漏。在AIM 3中，我们将通过确定流入和外排转运蛋白的表达和活性，评估屏障泄漏以及监测癫痫发作频率，持续时间和严重性，评估大鼠慢性癫痫模型中CPLA2抑制对癫痫发作负担的治疗益处。拟议的研究具有创新性，因为它专注于一种考虑血脑屏障转运蛋白以及屏障泄漏的新综合策略，并且专门旨在修复障碍物以克服AED耐药性并减少癫痫发作。拟议的研究很重要，因为预期的结果可能会提供一种新的策略来改善耐药性癫痫患者的药物治疗。拟议的研究是转化的，因为CPLA2抑制剂正在开发中，我们的策略有可能被转化为诊所。