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.

项目摘要/摘要了解由arbovirus引起的神经系统疾病的发病机理对使用药物或疫苗疗法治疗病毒脑炎。裂谷热（RVF）是全球重要的新兴的蚊子传播疾病给人类和牲畜社区带来了重大风险。由于普遍存在的蚊子载体，全球传播的潜力很高，出现将导致巨大的经济损害（由于农业影响）以及恐惧和焦虑（由于人类疾病）。由RVFV引起的最细腻的临床疾病是脑炎，这会导致长期 50％的神经系统症状患者中幸存者的发病率和死亡。该提议建立了根据我们的初步数据的3个科学发现：1）有适当的脑病动物模型用野生型RVFV菌株感染后； 2）细胞因子，趋化因子和基质的过量生产金属蛋白酶（MMP）与神经疾病发作相关； 3）用抗病毒治疗治疗药物favipiravir是必要的，但不足以保护动物免受致命神经系统疾病的侵害。综上所述，该提议的目的是了解细胞因子和MMP介导的宿主的作用 RVF引起的神经系统疾病的炎症反应，其最终目的是设计治疗预防神经病理学的干预措施。我们将使用三个补充特定目标来解决这一目标：在AIM 1中，我们将确定细胞因子和MMP调节RVF CNS的动力学机制炎。 AIM 2将开发新型的体外建模系统，以定义RVFV-CNS细胞相互作用和屏幕治疗候选人。 AIM 3将测试相关动物模型中的新型治疗方案。这提案将导致对免疫病理学对RVF神经系统疾病的贡献的理解。重要的是，我们将确定一种暴露后治疗方案，以防止神经RVF。这在这种新兴病原体流行的情况下，提案代表了关键步骤。