Neuroprotective anti-inflammatory drugs as a novel combination therapy for neurological Rift Valley Fever

神经保护性抗炎药物作为神经裂谷热的新型联合疗法

• 批准号: 9915980
• 负责人: Amy L Hartman
• 金额: $ 33.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915980
• 关键词: Acute; Address; Affect; Africa; Agriculture; Animal Disease Models; Animal Model; Animals; Anti-Inflammatory Agents; Antiviral Agents; Anxiety; Arbovirus Infections; Arboviruses; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Brain Diseases; CCL2 gene; Cell Communication; Cell Culture System; Cells; Cellular Assay; Central Nervous System Viral Diseases; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Communities; Culicidae; Data; Dengue; Disease; Disease Outbreaks; Disease Outcome; Disease model; Drug usage; Ebola; Economics; Encephalitis; Epidemic; Event; Exposure to; Fever; Fright; Future; Gelatinase B; Goals; Hemorrhage; Hepatic; Human; Imaging Techniques; Immune; Immunocompetent; Immunomodulators; Industry; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza; Kinetics; Lewis Blood-Group System; Livestock; Macrophage Colony-Stimulating Factor; Matrix Metalloproteinases; Mediating; Middle East; Modeling; Monkeys; Morbidity - disease rate; Nervous System Trauma; Neuraxis; Neurologic; Neurologic Symptoms; Neurons; Neuroprotective Agents; Oncology; Onset of illness; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Primary Cell Cultures; Production; Public Health; Rattus; Regimen; Rift Valley Fever; Rift Valley fever virus; Risk; Role; Survivors; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Protocols; Vaccine Therapy; Vaccines; Viral; Viral Encephalitis; Virulent; Virus; Virus Replication; ZIKA; blood-brain barrier disruption; cell type; chemokine; cytokine; design; effective therapy; human disease; immunopathology; in vitro Model; induced pluripotent stem cell; nervous system disorder; neuron apoptosis; neuropathology; novel; novel therapeutics; pathogen; prevent; public health emergency; stem cells; therapeutic candidate; vector mosquito

PROJECT SUMMARY/ABSTRACT Understanding the pathogenesis of neurological disorders caused by arboviruses is fundamental to the treatment of viral encephalitis using drug or vaccine therapy. Rift Valley Fever (RVF) is a globally-important emerging mosquito-transmitted disease that presents a significant risk to humans and livestock communities. The potential for global spread is high due to the pervasive mosquito vectors, and emergence would cause considerable economic damage (due to the agricultural impact) as well as fear and anxiety (due to human illness). The most understudied clinical disease caused by RVFV is encephalitis, which causes long-term morbidity in survivors as well as death in 50% of patients with neurological symptoms. This proposal is founded upon 3 scientific findings from our preliminary data: 1) There are appropriate encephalitic disease animal models after infection with a wild-type virulent strain of RVFV; 2) Overproduction of cytokines, chemokines, and matrix metalloproteinases (MMPs) correlates with neurological disease onset; and 3) Treatment with the antiviral therapeutic drug favipiravir is necessary but not sufficient to protect animals from lethal neurological disease. Taken together, the objective of this proposal is to understand the role of cytokine and MMP-mediated host inflammatory response in RVF-induced neurological disease, with the ultimate goal of designing therapeutic interventions to prevent neuropathology. We will address this objective using three complementary specific aims: In Aim 1, we will determine the kinetic mechanisms by which cytokines and MMPs modulate RVF CNS inflammation. Aim 2 will develop novel in vitro modeling systems to define RVFV-CNS cell interactions and screen therapeutic candidates. Aim 3 will test novel therapeutic regimens in a relevant animal model. This proposal will result in an understanding of the contribution of immunopathology to RVF neurological disease. Importantly, we will have identified a post-exposure treatment regimen to protect from neurological RVF. This proposal represents a critical step in the event of an epidemic of this emerging pathogen.

项目总结/摘要 了解虫媒病毒引起的神经系统疾病的发病机制是研究虫媒病毒引起的神经系统疾病的基础。 使用药物或疫苗疗法治疗病毒性脑炎。裂谷热（RVF）是一种全球性的重要疾病。 新出现的蚊子传播的疾病，对人类和牲畜社区构成重大风险。 由于蚊子媒介无处不在，全球传播的可能性很高， 相当大的经济损失（由于农业的影响）以及恐惧和焦虑（由于人类 病）。RVFV引起的临床疾病中研究最少的是脑炎， 存活者的发病率以及50%有神经系统症状的患者的死亡率。这项建议是建立在 根据我们的初步资料得出3个科学结论：1）存在合适的脑炎动物模型 用RVFV的野生型强毒株感染后; 2）细胞因子、趋化因子和基质的过度产生 金属蛋白酶（MMPs）与神经系统疾病发作相关;和3）用抗病毒药物治疗 治疗药物法匹拉韦是必要的，但不足以保护动物免受致命的神经系统疾病。 综上所述，本建议的目的是了解细胞因子和MMP介导的宿主的作用， RVF诱导的神经系统疾病的炎症反应，最终目标是设计治疗 预防神经病理学的干预措施。我们将通过三个互补的具体目标来实现这一目标： 在目标1中，我们将确定细胞因子和基质金属蛋白酶调节RVF CNS的动力学机制 炎症目的2将开发新的体外建模系统，以确定RVFV-CNS细胞相互作用， 筛选治疗候选人。目标3将在相关动物模型中测试新的治疗方案。这 这项建议将有助于了解免疫病理学对裂谷热神经系统疾病的影响。 重要的是，我们将确定一种暴露后治疗方案，以防止神经性裂谷热。这 该提案是在这种新出现的病原体流行的情况下迈出的关键一步。