Project 1: Reduction of Pro-Inflammatory Signaling

项目 1：减少促炎症信号传导

基本信息

批准号：
10684082
负责人：
Pamela J Lein
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/10684082
关键词：
Acute Address Adult Adverse effects Alzheimer&apos s disease model Animals Anti-Inflammatory Agents Astrocytes Atropine Attenuated Behavior Behavior assessment Benzodiazepines Biological Markers Blood Blood brain barrier dysfunction Brain Brain region Chemicals Chronic Clinical Cognitive Cognitive deficits Collaborations Convulsants Coxibs Cyclic AMP Data Development Dose Electroencephalography Enzyme Inhibition Epilepsy Epileptogenesis Epoxide hydrolase FDA approved Face Female Gliosis Goals HMGB1 gene Histology Homologous Gene Human IL8 gene Impaired cognition Incidence Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-1 Receptors Interleukin-1 beta Interleukin-6 Intoxication Isoflurophate Laboratories Lead Life Link Magnetic Resonance Imaging Measures Medical Research Memory Loss Microglia Minocycline Modeling Monitor Morbidity - disease rate Motor Natural History Nerve Degeneration Neurologic Neurologic Deficit Neurological outcome Organophosphates Outcome Oximes Parkinson Disease Pathology Pathway interactions Pharmaceutical Preparations Phenotype Pilocarpine Positron-Emission Tomography Pre-Clinical Model Prostaglandins Rattus Recurrence Research Institute Resolution Rest Risk STAT3 gene Safety Seizures Signal Transduction Signaling Molecule Soman Status Epilepticus Stroke Survivors Testing Therapeutic Treatment Efficacy acute care anakinra antagonist astrogliosis chemical threat cognitive function cyclooxygenase 2 improved in vivo imaging lipid mediator lipidome male medical countermeasure mineralization neuroinflammation neuropathology neuroprotection novel therapeutics predictive marker prevent response small molecule inhibitor spatiotemporal standard of care therapeutic candidate therapeutic target

项目摘要

Project Summary – Project 1 Convulsant chemical threat agents, such as the organophosphates (OPs) diisopropylfluorophosphate (DFP) and soman, can trigger seizures that progress to life-threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including spontaneous recurrent seizures (SRS) and mild-to-severe memory loss. Current medical countermeasures fail to sufficiently protect against these long-term neurological deficits. Project 1 will use a well-established rat model of acute DFP intoxication to test the hypothesis that therapies that promote resolution of inflammation when administered as adjuncts to standard of care will mitigate the long-term, adverse neurological consequences of acute OP intoxication. The scientific premise for this hypothesis includes experimental evidence that: (1) acute OP intoxication triggers a robust neuroinflammatory response in multiple brain regions that persists for up to 6 months; and (2) pro-inflammatory signaling is causally linked to epileptogenesis and cognitive dysfunction in non-OP models. We will focus our initial efforts on lipid mediators of inflammation. Our analyses of the brain lipidome in rats acutely intoxicated with DFP suggests two potential therapeutic approaches: inhibiting cyclooxygenase-2 (COX-2) to block the formation of prostaglandins, and inhibiting the enzyme soluble epoxide hydrolase (sEH) to stabilize anti-inflammatory lipid mediators. A small molecule inhibitor of sEH (sEHI) developed at UC Davis has been shown to significantly attenuate SRS in preclinical models of pilocarpine-induced epilepsy, improve cognitive function in preclinical models of Alzheimer’s disease (AD), and reduce pathology in models of AD, stroke and Parkinson’s disease. Our preliminary data suggest that sEHI also mitigates neuroinflammation and terminates SRS in the rat DFP model. Our goals are to: (1) Characterize the spatiotemporal profile of neuroinflammation in male and female rats following acute DFP intoxication in order to identify therapeutic targets, determine therapeutic windows, and develop translatable biomarkers of inflammation that predict SRS and/or cognitive dysfunction. (2) Evaluate the neuroprotective efficacy of sEHI and other compounds that target dysregulated inflammatory mediators in male and female rats acutely intoxicated with DFP. (3) Determine the safety of therapeutic lead(s) and their efficacy in protecting against adverse neurological consequences in a rat model of acute soman intoxication. If successful, Project 1 will identify novel therapeutic lead(s) that improve long-term neurological outcomes when used as adjuncts to standard of care, as well as biomarkers that identify individuals at increased risk for developing SRS and/or cognitive deficits following acute OP intoxication.

项目摘要 - 项目1 抽搐的化学威胁药，例如有机磷酸盐（OPS）二异丙氟磷酸酯（DFP）和索曼（Soman）可以触发癫痫发作，这些癫痫发作会发展为威胁生命的癫痫持续状态（SE）。幸存者面临着重要的长期发病率，包括自发的复发性癫痫发作（SRS）和轻度至重度记忆丧失。当前的医学对策无法正确防止这些长期神经系统缺陷。项目1将使用公认的急性DFP肠毒性大鼠模型来检验促进疗法的假设当作为护理标准的辅助剂给药时，炎症的分辨率将减轻长期的对手急性OP中毒的神经系统后果。该假设的科学前提包括实验证据表明：（1）急性OP INTOOCIOT触发多个的鲁棒神经炎症反应持续长达6个月的大脑区域；（2）促炎信号有时与非OP模型中的癫痫发生和认知功能障碍。我们将最初的努力集中在脂质介质上炎症。我们对DFP急性陶醉大鼠脑脂多组的分析表明了两个潜力治疗方法：抑制环氧合酶-2（COX-2）阻止前列腺素的形成和抑制酶固体环氧水解酶（SEH）以稳定抗炎脂质介质。一个小在UC Davis开发的SEH（SEHI）的分子抑制剂已显示出显着减弱SRS 毛果石诱导的癫痫的临床前模型，改善阿尔茨海默氏临床前模型的认知功能疾病（AD），并减少AD，中风和帕金森氏病模型中的病理。我们的初步数据建议SEHI还减轻神经炎症并在大鼠DFP模型中终止SRS。我们的目标是：（1）表征急性DFP后雄性和雌性大鼠神经炎症的时空特征陶醉以识别治疗靶标，确定治疗窗口并开发可翻译的预测SRS和/或认知功能障碍的炎症生物标志物。（2）评估神经保护靶向雄性和雌性大鼠炎症介质失调的SEHI和其他化合物的效率用DFP急性陶醉。（3）确定治疗铅的安全性及其保护的效率在急性SOMAN中毒大鼠模型中反对不良神经系统后果。如果成功，项目1 将确定新的热铅（S），这些铅在用作辅助的情况下改善长期神经系统结果护理标准以及识别患者患有SRS和/或急性OP中毒后的认知防御能力。