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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.

项目摘要-项目2 有机磷酸盐（OP）如二异丙基氟磷酸盐（DFP）是惊厥性化学威胁剂，可引发癫痫发作，发展为危及生命的癫痫持续状态（SE）。当前标准治疗（SOC）急性暴露的重点是终止SE，但不一定是对长期暴露的保护。在幸存者中经常观察到不良的神经系统后果。血脑屏障（BBB）功能障碍作为一种急性OP中毒的后果尚未得到严格的评价，尽管可能与BBB有关在预防各种脑损伤后可能出现的神经病理学方面的完整性，中毒此外，预防或逆转血脑屏障破坏以减轻血脑屏障损伤的治疗策略的功效也有待进一步研究。 OP诱导的胆碱能危象后的自发性复发性癫痫发作（SRS）和认知功能障碍尽管迫切需要找到新的治疗方法，可以解决为了解决这些主要差距，项目2将使用一个完善的DFP中毒大鼠模型，检验以下假设：当作为SOC的替代品给药时，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。科学前提支持这一假说包括初步证据，证明：（1）血脑屏障渗漏和存在用钆对比MRI测量DFP急性中毒大鼠脑中的微血管;（2）急性DFP中毒后BBB破坏的已知介质活性增加，与 TGFβ信号可能参与DFP引发的长期不良神经效应的假设中毒;（3）阻断钙蛋白酶蛋白水解活性可预防癫痫发生。我们的目标是描述急性OP中毒后BBB功能障碍的时空进展， OP诱导的BBB/神经血管功能障碍的治疗靶点的机制和参与并确定治疗候选物（化合物10357）的功效、安全性和广谱活性 - 促进派-1-tPA+ GFAP-星形胶质细胞、IPW-5371 - TGFβ受体1和2抑制剂和MDL-28170的细胞死亡 - 钙蛋白酶抑制剂）。如果成功，这个项目可能会改变游戏规则，因为它将决定翻译用于鉴定处于发展慢性不良神经作用风险中的个体的生物标志物，作为SOC的后续治疗时，可改善长期神经系统结局的治疗候选物。此外，鉴于OP中毒模型与其他癫痫一般模型之间的相似性，所发现的可能的靶点和/或疗法可对其它致癫痫性损伤具有更广泛的应用。实验设计的特殊集成，包括DFP模型和自动读数，所有三个项目的合作将产生有意义的互动，并促进数据共享，以产生更大的影响。