Project 2: Protection of Blood-Brain Barrier Function

项目二：血脑屏障功能保护

基本信息

批准号：
10684086
负责人：
ANGIE GELLI
金额：
$ 49.11万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684086
关键词：
Acute Address Albumins Alteplase Animals Astrocytes Behavior assessment Biochemical Biological Markers Blood - brain barrier anatomy Blood brain barrier dysfunction Blood coagulation Brain Calpain Cell Death Chemicals Chronic Convulsants Data Detection Electroencephalography Epilepsy Epileptogenesis Experimental Designs Extravasation Female Fluorescent Dyes Fostering Frequencies Functional disorder Gadolinium Glial Fibrillary Acidic Protein Goals Hemorrhage Histologic Human Image Impaired cognition Individual Injury Intoxication Isoflurophate Life Link Literature Magnetic Resonance Imaging Maps Measures Mediating Mediator Microglia Modeling Molecular Motor Nerve Degeneration Neurologic Neurologic Deficit Neurologic Effect Neurological outcome Organophosphates Pathway interactions Pericytes Permeability Plasminogen Activator Inhibitor 1 Poison Poisoning Property Publishing Rattus Recurrence Risk Role Safety Seizures Signal Transduction Status Epilepticus Survivors Testing Therapeutic Transforming Growth Factor beta Treatment Efficacy acute care biomarker identification blood-brain barrier disruption blood-brain barrier function brain endothelial cell cadherin 5 calpain inhibitor chemical threat cholinergic cognitive function data sharing efficacy evaluation functional outcomes improved in vivo in vivo imaging inhibitor macromolecule male molecular marker neuroinflammation neurological pathology neuroprotection neurovascular neurovascular unit novel therapeutic intervention novel therapeutics occludin pharmacologic prevent receptor small molecule inhibitor spatiotemporal standard of care therapeutic candidate therapeutic target tool toxic organophosphate insecticide exposure transcytosis translational potential wireless sensor

项目摘要

Project Summary – Project 2 Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) are convulsant chemical threat agents that can trigger seizures that progress to life-threatening status epilepticus (SE). The current standard of care (SOC) for acute exposure focuses on the termination of SE but not necessarily on the protection against long-term adverse neurological consequences often observed in survivors. Blood-brain barrier (BBB) dysfunction as a consequence of acute OP intoxication has not been rigorously evaluated despite the possible relevance of BBB integrity in preventing neurological pathologies that can arise following various brain insults including chemical toxicosis. Moreover, the efficacy of therapeutic strategies that prevent or reverse BBB disruption to mitigate spontaneous recurrent seizures (SRS) and cognitive dysfunction following OP-induced cholinergic crisis has not been explored, even though there is a dire need to find new therapies that can address the limitations of the current SOC. To tackle these major gaps, Project 2 will use a well-established rat model of DFP intoxication to test the hypothesis that therapies that reverse BBB dysfunction when administered as adjuncts to SOC will mitigate the long-term, adverse neurological consequences of OP intoxication. The scientific premise supporting this hypothesis includes preliminary evidence demonstrating: (1) BBB leakage and the presence of microhemorrhages in brains of rats acutely intoxicated with DFP as measured by gadolinium-contrast MRI; (2) increased activity of known mediators of BBB disruption following acute DFP intoxication, consistent with the hypothesis that TGFβ signaling could be involved in the long-term adverse neurological effects triggered by DFP intoxication; and (3) blocking calpain proteolytic activity may prevent epileptogenesis. Our goals are to characterize the spatiotemporal progression of BBB dysfunction following acute OP intoxication, identify the mechanisms and engagement of therapeutic targets contributing to OP-induced BBB/neurovascular dysfunction and determine the efficacy, safety and broad-spectrum activity of the therapeutic candidates (compound 10357 - promotes cell death of PAI-1-tPA+GFAP-astrocytes, IPW-5371 - TGFβ receptor 1 & 2 inhibitor, and MDL-28170 - calpain inhibitor). If successful, this Project could be a game-changer, since it will determine translational biomarkers for identifying individuals at risk of developing chronic adverse neurological effects and identify therapeutic candidates to improve long-term neurological outcome(s) when used as adjunctive therapy to SOC. Moreover, given the similarities between the OP intoxication model and other general models of epilepsy, the possible targets and/or therapies discovered could have broader application toward other epileptogenic injuries. The exceptional integration of the experimental design, including the DFP model and the behavorial readouts, across all three Projects will generate meaningful interactions and foster data sharing for greater impact.

项目总结 – 项目 2 有机磷酸酯 (OP)，例如氟磷酸二异丙酯 (DFP) 是令人惊厥的化学威胁剂，可能引发癫痫发作并发展为危及生命的癫痫持续状态 (SE) 目前的护理标准 (SOC)。对于急性暴露，重点是终止 SE，但不一定是针对长期暴露的保护幸存者中经常观察到血脑屏障（BBB）功能障碍的不良神经后果。尽管 BBB 可能具有相关性，但急性 OP 中毒的后果尚未经过严格评估预防各种脑损伤（包括化学损伤）后可能出现的神经病理学的完整性此外，预防或逆转血脑屏障破坏的治疗策略的有效性。 OP 引起的胆碱能危象后自发性复发性癫痫发作 (SRS) 和认知功能障碍尚未出现尽管迫切需要找到可以解决现有技术局限性的新疗法为了解决这些主要差距，项目 2 将使用成熟的 DFP 中毒大鼠模型来解决这一问题。检验以下假设：当作为 SOC 的辅助药物施用时，逆转 BBB 功能障碍的疗法将减轻OP中毒的长期不良神经后果支持的科学前提。该假设包括初步证据，证明：(1) BBB 泄漏和存在通过钆对比 MRI 测量急性 DFP 中毒大鼠脑部微出血 (2) 急性 DFP 中毒后已知 BBB 破坏介质的活性增加，与假设 TGFβ 信号传导可能参与 DFP 引发的长期不良神经系统影响中毒；（3）阻断钙蛋白酶的蛋白水解活性可以预防癫痫发生。描述急性 OP 中毒后 BBB 功能障碍的时空进展特征，确定 OP 诱导的 BBB/神经血管功能障碍的机制和治疗靶点的参与并确定候选治疗药物（化合物 10357）的功效、安全性和广谱活性 - 促进 PAI-1-tPA+GFAP-星形胶质细胞、IPW-5371 - TGFβ 受体 1 和 2 抑制剂以及 MDL-28170 的细胞死亡 - 钙蛋白酶抑制剂）。如果成功，该项目可能会改变游戏规则，因为它将决定转化。识别有发生慢性不良神经系统影响风险的个体的生物标志物，并确定用作 SOC 的辅助治疗时可改善长期神经治疗结果的候选者。此外，考虑到 OP 中毒模型与其他一般癫痫模型的相似性，发现的可能目标和/或疗法可能对其他致癫痫性损伤有更广泛的应用。实验设计的卓越集成，包括 DFP 模型和行为读数，所有三个项目将产生有意义的互动并促进数据共享以产生更大的影响。