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），例如二异丙氟磷酸磷酸盐（DFP）是抽搐的化学威胁药物可以触发癫痫发作的癫痫发作（SE）。当前的护理标准（SOC）因为急性暴露的重点是终止SE，但不一定是针对长期的保护不良神经系统后果经常在生存中观察到。血脑屏障（BBB）功能障碍作为一个尽管BBB可能相关，但急性OP中毒的结果尚未得到严格评估在包括化学物质在内的各种大脑侮辱之后，可以预防可能出现的神经病理学的完整性有毒性。此外，预防或反向BBB中断的理论策略的效率在操作引起的胆碱能危机之后的赞助复发性癫痫发作（SRS）和认知功能障碍尚未即使有迫切需要找到可以解决该限制的新疗法，也被探讨了当前的SoC。为了解决这些主要差距，项目2将使用良好的DFP中介绍大鼠模型检验以下假设：当作为辅助辅助施用时，逆转BBB功能障碍的疗法将减轻OP中毒的长期不良神经系统后果。科学前提支持该假设包括证明：（1）BBB泄漏和存在的初步证据通过Gadolinium-Contrast MRI测量的DFP急性陶醉的大鼠大脑中的微毛发；（2）急性DFP进化后，已知的BBB中断介体的活性增加，与假设TGFβ信号传导可能与DFP触发的长期不良神经效应有关中毒；（3）阻断钙蛋白酶的蛋白水解活性可能预防癫痫发生。我们的目标是表征急性OP中毒后BBB功能障碍的时空进展，确定导致OP诱导的BBB/神经血管功能障碍的治疗靶标的机制和参与度并确定治疗候选物的效率，安全性和广谱活动（化合物10357 - 促进PAI-1-TPA+GFAP-ASSTROCYTES的细胞死亡，IPW-5371-TGFβ受体1和2抑制剂和MDL-28170 - 钙蛋白酶抑制剂）。如果成功的话，这个项目可能会改变游戏规则，因为它将决定翻译生物标志物，用于识别有发展慢性不良神经系统效应风险的人并识别当用作SOC的辅助治疗时，治疗候选者可以改善长期神经系统结果。此外，鉴于OP Incontication模型与其他癫痫的一般模型之间的相似之处，发现的靶标和/或疗法可能对其他癫痫损伤具有更广泛的应用。实验设计的特殊整合，包括DFP模型和遗嘱读数，在所有三个项目中，将产生有意义的交互并促进数据共享，以提高影响。