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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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疾病给人类和牲畜群带来重大风险。由于蚊子媒介普遍存在，全球传播的可能性很高，出现后会导致相当大的经济损失（由于农业影响）以及恐惧和焦虑（由于人类活动）疾病）。由 RVFV 引起的、研究最多的临床疾病是脑炎，它会导致长期幸存者发病率以及 50% 有神经系统症状的患者死亡。本提案成立根据我们初步数据得出的 3 项科学发现： 1) 存在合适的脑炎疾病动物模型感染RVFV野生型强毒株后； 2) 细胞因子、趋化因子和基质的过量产生金属蛋白酶 (MMP) 与神经系统疾病的发病相关； 3) 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。总而言之，该提案的目的是了解细胞因子和 MMP 介导的宿主的作用 RVF 诱发的神经系统疾病中的炎症反应，最终目标是设计治疗方法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 MMP 调节 RVF CNS 的动力学机制炎。目标 2 将开发新型体外建模系统来定义 RVFV-CNS 细胞相互作用和筛选治疗候选者。目标 3 将在相关动物模型中测试新的治疗方案。这该提案将有助于了解免疫病理学对裂谷热神经系统疾病的贡献。重要的是，我们将确定一种暴露后治疗方案来预防神经性裂谷热。这该提案是在这种新兴病原体流行时迈出的关键一步。