Central Motivation of Depression; An Expanded Kynurenine Theory

抑郁症的核心动机；

• 批准号: 9979974
• 负责人: Robert H. McCusker
• 金额: $ 45.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-06 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979974
• 关键词: Acute; Adaptive Immune System; Adult; Advanced Development; Affect; Animal Behavior; Animal Model; Anxiety; Astrocytes; Attenuated; Behavior; Behavioral; Brain; C57BL/6 Mouse; Catabolism; Cells; Central Nervous System Infections; Central Nervous System Viral Diseases; Child; Cicatrix; Clinical; Clinical Research; Coxsackie Viruses; Cytolysis; Data; Development; Dioxygenases; Disease; Disease Outbreaks; Encephalitis; Encephalopathies; Enterovirus; Enzymes; Family Picornaviridae; Family member; Flaviviridae; Future; Genetic; Genetic Models; Goals; Herpesviridae; Human; Immune response; Immune system; Immunology; Impaired cognition; Impairment; Incidence; Infection; Inflammation; Inflammatory; Innate Immune System; Japanese encephalitis virus; Knock-out; Kynurenic Acid; Kynurenine; Lead; Life; Life Experience; Link; Mediating; Mental Depression; Microglia; Modeling; Modification; Molecular; Molecular Biology; Molecular Target; Motivation; Motor; Mouse Strains; Mus; Nerve Degeneration; Nervous System Physiology; Neuroglia; Neurologic; Neurologic Deficit; Neurons; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pre-Clinical Model; Process; Production; Proteins; Public Health; Quinolinic Acid; Refractory; Reporting; Research; Risk; Role; Seizures; Sensory; Series; Simplexvirus; Source; Specificity; St. Louis Encephalitis Virus; Survivors; Symptoms; TMEV; Testing; Tonic - clonic seizures; Translational Research; Tryptophan; Tryptophan Metabolism Pathway; Tumor-infiltrating immune cells; United States; Viral; Viral Encephalitis; Viral Pathogenesis; Viral Physiology; Virus; Virus Diseases; Virus Replication; West Nile virus; ZIKA; Zika Virus; base; cell type; cellular targeting; comorbidity; design; effective therapy; experimental study; fighting; global health; immune activation; immune function; indexing; indoleamine; inhibitor/antagonist; interdisciplinary approach; macrophage; mouse model; multidisciplinary; neuron loss; neurotoxic; novel; novel therapeutics; pathogen; prevent; public health relevance; theories; therapy development

Project Summary Encephalitis attributed to viral infection is often refractory to established drugs. Enteroviruses (Picornaviridae) are a common cause of encephalitis with neurological sequelae; as are Arborviruses (West Nile and Zika that are emerging infectious pathogens spreading across the United States). Viral encephalitis impairs neurological function that may lead to acute seizures (ictogenesis), neurodegeneration and persistent comorbid conditions including cognitive impairment, depression and anxiety. Therefore, finding new and novel therapeutics is important for public health. Only recently was a suitable animal model developed to investigate how viral encephalitis causes this neuropathogenic sequelae. When infected with Theiler's murine encephalomyelitis virus (TMEV, a Picornavirus), C57BL/6 mice survive the infection, but develop acute seizures followed by persistent comorbid conditions including cognitive impairment and anxiety. Activation of the innate immune system is strongly implicated in development of these symptoms. Although modifications are frequently investigated as a means to limit damage to the brain, this immune response is designed and indeed critical to fight the infection. Effective therapies are needed to prevent neurological sequelae without compromising immune function. We have uncovered two proteins that appear to meet these criteria. The indoleamine 2,3-dixogenases (Ido's: Ido1 and Ido2) encode inflammation-dependent rate-limiting enzymes that initiate metabolism of tryptophan to kynurenine. Kynurenine is then metabolized in a cell-specific manner to generate either neurotoxic/seizure- inducing or neuroprotective/anti-seizure metabolites. By genetic modification of the Ido's, we have generated mice with diminished or enhanced neurological sequelae following viral encephalitis. We propose to identify the source of Ido responsible for these sequelae. To achieve this goal, we will conduct a series of rigorous multidisciplinary (ex vivo, genetic and pharmaceutical) experiments with the TMEV model of encephalitis. This mouse model recapitulates clinical observations including neurodegeneration, formation of a glial scar and the development of spontaneous seizures. Specific Aim 1 will characterize in detail the ability of viral infection to modulate Ido activity within cells implicated in the progression of encephalitis. Specific Aim 2 will define which cell's Ido activity is mediating ictogenesis and neurodegeneration. Specific Aim will characterize Ido-dependent persistent behaviors. And Specific Aim 4 will initiate translational research to examine the ability of Ido-inhibitors to attenuate neurological sequelae associated with encephalitis. Our data support a paradigm shifting hypothesis where changes in Ido activity has the potential to prevent viral-induced neurological sequelae without affecting the immune system's ability to fight infection. Data generated from the proposed experiments should have broad implications across all types of encephalitis. Understanding the molecular pathway and cellular specificity by which this process occurs will create an advanced understanding of the mechanisms operating during viral and inflammatory diseases and identify cellular and molecular targets for the development of novel therapies.

项目摘要 归因于病毒感染的脑炎通常对现有药物无效。肠道病毒(短小航病科) 是脑炎和神经后遗症的常见原因；虫媒病毒(西尼罗河病毒和寨卡病毒， 是在全美传播的新出现的传染病病原体)。病毒性脑炎损害神经功能 可能导致急性癫痫发作(细胞分裂)、神经退行性变和持续的共病情况的功能 包括认知障碍、抑郁和焦虑。因此，寻找新的治疗方法是 对公众健康很重要。直到最近才开发出一种合适的动物模型来研究病毒是如何 脑炎会导致这种神经致病后遗症。感染泰勒氏小鼠脑脊髓炎病毒时 (TMEV，一种短小核糖核酸病毒)，C57BL/6小鼠在感染后存活，但出现急性癫痫发作，随后持续 包括认知障碍和焦虑在内的并存情况。先天免疫系统的激活 与这些症状的发展密切相关。尽管经常将修改作为 为了限制对大脑的损害，这种免疫反应是专门设计的，确实对抗击感染至关重要。 在不损害免疫功能的情况下，需要有效的治疗方法来预防神经后遗症。我们 发现了两种似乎符合这些标准的蛋白质。吲哚胺2，3-二氧基酶(IDO‘s：IDO1 和Ido2)编码炎症依赖的限速酶，启动色氨酸的新陈代谢 犬尿氨酸。犬尿氨酸然后以细胞特异性的方式代谢，产生神经毒性/癫痫- 诱导或神经保护/抗癫痫的代谢物。通过对伊多人进行基因改造，我们已经产生了 病毒性脑炎后神经后遗症减轻或增强的小鼠。我们建议确定 Ido的来源对这些后遗症负有责任。为了实现这一目标，我们将进行一系列严格的 脑炎TMEV模型的多学科(体外、遗传和药物)实验。这 小鼠模型总结了临床观察，包括神经变性，胶质瘢痕的形成和 自发性癫痫的发展。具体目标1将详细描述病毒感染的能力 调节细胞内碘的活性与脑炎的进展有关。具体目标2将定义 细胞的IDO活性参与细胞分裂和神经退行性变。特定的目标将成为Ido依赖的特征 持久的行为。而特殊目标4将启动翻译研究，以检查IDO抑制剂的能力 以减轻与脑炎相关的神经后遗症。我们的数据支持范式转换假说 IDO活性的变化有可能预防病毒引起的神经后遗症而不影响 免疫系统抵抗感染的能力。从拟议的实验中产生的数据应该具有广泛的 对所有类型的脑炎都有影响。了解分子途径和细胞特异性 这一过程的发生将使我们更深入地了解病毒和 并确定用于开发新疗法的细胞和分子靶点。