Virus-Host Interactions that Lead to Epilepsy

导致癫痫的病毒-宿主相互作用

基本信息

批准号：
8387015
负责人：
Robert S Fujinami
金额：
$ 30.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387015
关键词：
Acute Adenoviruses Affect American Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antiepileptic Agents Apoptosis Behavior Biological Models Brain Brain Part C57BL/6 Mouse Cells Central Nervous System Infections Central Nervous System Viral Diseases Cessation of life Chimera organism DNA Nucleotidylexotransferase Development Disease Electric Stimulation Encephalitis Encephalitis Viruses Enterovirus 71 Epilepsy Epileptogenesis Etiology Experimental Animal Model Family Picornaviridae Herpesviridae Hippocampus (Brain)Human Immune Immune response Immunodeficient Mouse Incidence Individual Infection Inflammation Interferons Interleukin-1 Interleukin-6 Intervention Investigation Lead Life Limbic System Modeling Mus Neuraxis Neuronal Dysfunction Neurons Oryctolagus cuniculus Pathogenesis Patients Pharmaceutical Preparations Phase Plague Prevention Production Public Health Pyramidal Cells Rattus Recurrence Refractory Relative (related person)Reporting Respiratory syncytial virus Risk Risk Factors Role Rotavirus Route Seizures Staining and Labeling Staining method Stains Structure TMEV Temporal Lobe Epilepsy Testing Tumor Necrosis Factor-alpha Viral Viral Antigens Viral Encephalitis Virus Virus Diseases cytokine influenzavirus killings mouse model mutant neuron loss neurotoxic neurotropic novel novel strategies novel therapeutic intervention novel therapeutics olfactory bulb public health relevance suicidal risk virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Viral infections of the central nervous system (CNS) can result in encephalitis. Viral encephalitis is a risk factor for epilepsy. Epilepsy has an incidence of about 1 to 3% and affects about 2.5 million Americans and more than 50 million individuals worldwide. Seizures result from imbalances between excitatory and inhibitory inputs within the brain. Encephalitis and resulting damage to the CNS can alter these inputs. Infection- initiated seizure disorders are often refractory to many established anti-epileptic drugs. Approximately 30% of individuals with epilepsy are refractory to currently existing anti-seizure medications. Therefore, finding new biological models for epilepsy and potentially new therapeutics are important for the public health. Different virus infections can cause encephalitis that result in seizures. These viruses include herpes viruses such as human herpes virus type-6, influenza viruses, rotaviruses, adenovirus, respiratory syncytial virus and picornaviruses. For example, the human picornavirus, Enterovirus 71, causes encephalitis where patients often present with seizures. A problem that has plagued this field is that a good experimental animal model is not available to investigate how virus encephalitis can lead to epilepsy. Previous animal models have infected rabbits, rats and mice with different viruses. These animals develop acute encephalitis and develop seizures but succumb to the infection. Theiler's murine encephalomyelitis virus (TMEV) is a neurotropic picornavirus. We have developed a new and novel model where infection of C57BL/6 mice with the Daniels virus (DAV) strain of TMEV leads to acute seizures between days 3 and 10 post infection. Mice recover but after a variable latent period mice start to have spontaneous seizures. This is the first infection driven model of temporal lobe epilepsy. We propose to test in Specific Aim 1 the hypothesis that direct virus infection of pyramidal cells of the hippocampus leads to the development of seizures. In Specific Aim 2 we hypothesize that DAV infection targets a cytokine storm to regions within the CNS that leads to neuronal dysfunction and death. Relevance: Up to 20% of individuals who survive viral encephalitis develop epilepsy. This model is the first infection driven model for epilepsy. Other animal models use electrical stimulation or neurotoxic substances that kill and/or alter neurons in different parts of the brain leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies using an anti- inflammatory approach. As mentioned above about 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new approaches are warranted.

描述（由申请人提供）：中枢神经系统（CNS）的病毒感染可能导致脑炎。病毒脑炎是癫痫的危险因素。癫痫病的发病率约为1-3％，全球约有250万美国人和超过5000万个人。癫痫发作是由于大脑内部兴奋性和抑制性投入之间的失衡而引起的。脑炎和对中枢神经系统的损害会改变这些输入。感染引发的癫痫发作通常对许多已建立的抗癫痫药物难治性。癫痫患者中约有30％对当前现有的抗塞氏菌药物难治性。因此，寻找用于癫痫和潜在新疗法的新生物学模型对公共卫生很重要。不同的病毒感染会导致脑炎导致癫痫发作。这些病毒包括疱疹病毒，例如人类疱疹病毒6型病毒，流感病毒，轮状病毒，腺病毒，呼吸道综合病毒和PICORNAVIRASE。例如，人picornavirus（肠病毒71）引起脑炎，患者经常出现癫痫发作。困扰该领域的一个问题是，一个良好的实验动物模型无法研究病毒脑炎如何导致癫痫。以前的动物模型已感染了不同病毒的兔子，大鼠和小鼠。这些动物患有急性脑炎并发作癫痫发作，但屈服于感染。 Theiler的鼠脑脊髓炎病毒（TMEV）是一种神经性picornavirus。我们已经开发了一种新的新型模型，其中C57BL/6小鼠患有Daniels病毒（DAV）TMEV菌株会导致感染后第3至10天之间的急性癫痫发作。小鼠恢复，但是在变化的潜在时期后，小鼠开始自发癫痫发作。这是颞叶癫痫的第一个感染驱动的模型。我们建议在特定目标中检验1个假说，即海马锥体细胞的直接病毒感染导致癫痫发育。在特定的目标2中，我们假设DAV感染靶向一场细胞因子风暴，导致CNS内的区域，导致神经元功能障碍和死亡。相关性：在病毒性脑炎中生存的个体中，多达20％的患者发展出癫痫。该模型是第一个用于癫痫的感染驱动模型。其他动物模型使用电刺激或神经毒性物质杀死和/或改变大脑不同部位的神经元，导致自发性癫痫发作。我们的病毒模型可能更重要，特别是使用抗炎症方法测试新的治疗策略。如上所述，大约30％的癫痫患者对现有的抗塞氏菌药物难治性，最近，FDA建议将警告附加到11例癫痫药物上，以披露自杀的风险。因此，有必要进行新的方法。