Treatment and Disease Markers for Alpha and Flaviviruses

α 病毒和黄病毒的治疗和疾病标志物

• 批准号: 7641031
• 负责人: John D Morrey
• 金额: $ 37.4万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641031
• 关键词: Animal Model; Animals; Antibodies; Benchmarking; Biochemical; Bioinformatics; Blood - brain barrier anatomy; Brain; Cerebral Ventricles; Cerebrospinal Fluid; Chemicals; Clinical; Clinical Chemistry; Clinical Markers; Clinical Trials; Communicable Diseases; Compatible; Contracts; Convection; Coupled; Cytology; Data; Development; Disease; Disease Marker; Disease Outcome; Electrophoresis; Encephalitis; Event; Excitatory Amino Acid Antagonists; Flavivirus; Hamsters; Human; Industry; Inflammation; Investigational Drugs; Label; Life; Modeling; Necrosis; Neurons; Nitric Oxide; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Proteins; Proteome; Publishing; Research; Route; Screening procedure; Serum; Serum Markers; Spectrophotometry; Staging; Technology; Therapeutic; Time; Two-Dimensional Gel Electrophoresis; United States National Institutes of Health; Universities; Utah; Viral; Viral Encephalitis; Virus; West Nile virus; Western Equine Encephalomyelitis; base; follow-up; neuron apoptosis; programs; therapy outcome

Our strategy has been to identify FDA-approved drugs or investigational new drugs (IND) that might be used in off-label applications to treat viral encephalitis so that the pathway to human treatment would be shorter. Preliminary data suggests that glutamate receptor antagonists, modulators of nitric oxide, or viralreactive antibodies might be used to treat viral encephalitis after the virus has entered the brain. The objective of this project is to identify biochemical, viral or cellular markers in the cerebrospinal fluid (CSF) or serum for benchmark pathological events in live animals that are needed for a) effectively treating viral encephalitis, b) determining the order and timing of these pathological events, c) clinically managing the treatment, and d) planning clinical trials. Additionally, the objective is to use these markers to appropriately treat West Nile virus (WNV) encephalitis and Western equine encephalitis (WEE) using FDA-approved drugs or IND identified in our current screening NIH contracts at USD. Specific Aim #1: Identify and correlate the time-course of viral expression, blood-brain-barrier (BBB) permeabilization, necrosis, neuron apoptosis and neuro-inflammation in specific portions of the brain and at different stages of disease. Markers for disease outcome and therapy in CSF and serum have not been adequately identified. Specific Aim #2: Compare CSF and serum 2D-gel electrophoresis proteins and classical clinical markers with disease parameters at different stages. Based on our preliminary results, proteins will be identified in CSF and serum at different stages of disease from uninfected and WNV- and WEE-infected hamsters using 2-D electrophoresis fluorescent-labeled protein technology (DICE). Disease protein-markers will be identified by mass spectrophotometry coupled with proteome bioinformatics. Specific Aim #3: Use CSF or serum markers to identify, and most effectively administer, therapies for WNV or WEE disease. Therapeutics will be evaluated in the hamster model at different stages of disease using clinical or CSF/serum markers and will be administered in the brain by convection-enhanced delivery (CED). FDA-approved or IND candidates showing efficacy will be communicated with University of Utah Infectious Disease Unit for possible off-label administration to WNV-infected patients or to companies with compatible technologies. Project interactions: This and other projects within the USU program will collaborate with the Infectious Disease unit at the U of U, with treatment of viral encephalitis, with aerolization of drugs and virus at the Animal Models Core, and with industry, i.e., IVAX Research and Axonix USA.

我们的策略是确定可能是FDA批准的药物或研究性新药（IND） 用于治疗病毒脑炎的标签外应用中 短。初步数据表明，谷氨酸受体拮抗剂，一氧化氮的调节剂或病毒反应性 病毒进入大脑后，抗体可用于治疗病毒脑炎。这 该项目的目的是识别脑脊液（CSF）或 活动物中基准病理事件的血清a）有效治疗病毒 脑炎，b）确定这些病理事件的顺序和时间，c）临床管理 治疗和d）计划临床试验。此外，目的是使用这些标记来适当 使用FDA批准 在我们目前的USD筛查NIH合同中确定的药物或IND。特定目标＃1：识别和 将病毒表达，血脑屏障（BBB）透化，坏死，神经元的时间顺序 在大脑的特定部分和疾病的不同阶段，凋亡和神经炎症。 CSF和血清中疾病结局和治疗的标记尚未得到充分鉴定。具体的 AIM＃2：比较CSF和血清2D-GEL电泳蛋白和经典临床标记 在不同阶段的疾病参数。根据我们的初步结果，将在CSF中鉴定蛋白质 以及来自未感染和WNV和Wee感染的仓鼠的疾病不同阶段的血清 电泳荧光标记的蛋白质技术（DICE）。疾病蛋白标志物将通过 质量分光光度计结合蛋白质组生物信息学。特定目标＃3：使用CSF或血清 标记以识别WNV或WEE疾病的疗法，并最有效地给予疗法。治疗学会 使用临床或CSF/血清标记物在疾病的不同阶段在仓鼠模型中进行评估 将通过对流增强输送（CED）在大脑中给药。 FDA批准或IND候选人 显示功效将与犹他大学传染病部门传达，以获得可能的非标签 对WNV感染的患者或具有兼容技术的公司进行管理。项目 互动：USU计划中的该项目和其他项目将与传染病合作 U的U的单位，并处理病毒性脑炎，并在动物处使用药物和病毒的气毒 模型核心，以及工业界，即Ivax Research和Axonix USA。