Central Motivation of Depression; An Expanded Kynurenine Theory

项目摘要 由病毒感染引起的脑炎通常对现有药物无效。肠道病毒（小核糖核酸病毒科） 是导致脑炎和神经系统后遗症的常见原因;树型病毒（西尼罗河病毒和寨卡病毒）也是如此， 新出现的传染性病原体正在美国蔓延）。病毒性脑炎损害神经系统 可能导致急性癫痫发作（发作发生）、神经变性和持续性共病的功能 包括认知障碍抑郁和焦虑因此，寻找新的和新颖的治疗方法是 对公众健康很重要。直到最近才发展出一种合适的动物模型来研究病毒 脑炎引起这种神经致病性后遗症。感染泰勒氏鼠脑脊髓炎病毒后 (TMEV，一种小核糖核酸病毒），C57 BL/6小鼠在感染后存活，但发生急性癫痫发作，随后持续性癫痫发作。 合并症包括认知障碍和焦虑。先天免疫系统的激活是 与这些症状的发展密切相关。虽然修改经常被调查作为一个 这种免疫反应是为了限制对大脑的损害，而且确实对对抗感染至关重要。 需要有效的治疗来预防神经系统后遗症而不损害免疫功能。我们 发现了两种符合这些标准的蛋白质。吲哚胺2，3-二氧化酶（Ido's：Ido 1 和Ido 2）编码炎症依赖性限速酶，其启动色氨酸的代谢， 犬尿氨酸犬尿氨酸然后以细胞特异性方式代谢，产生神经毒性/癫痫发作- 诱导或神经保护/抗癫痫代谢物。通过对伊多人的基因改造， 病毒性脑炎后神经系统后遗症减轻或加重的小鼠。我们建议确定 造成这些后遗症的原因。为了实现这一目标，我们将进行一系列严格的 用脑炎的TMEV模型进行多学科（离体、遗传和药学）实验。这 小鼠模型概括了临床观察结果，包括神经变性、胶质瘢痕的形成和 自发性癫痫发作。具体目标1将详细描述病毒感染的能力， 调节与脑炎进展有关的细胞内的Ido活性。具体目标2将定义 细胞的Ido活性介导了癫痫发作和神经退行性变。特定目标将表征Ido依赖性 持续的行为。具体目标4将启动转化研究，以检查Ido抑制剂的能力 以减轻与脑炎相关的神经后遗症。我们的数据支持一个范式转变的假设 其中Ido活性的变化有可能预防病毒诱导的神经系统后遗症，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具有广泛的 对所有类型脑炎的影响。了解分子途径和细胞特异性， 这一过程的发生将创造一个先进的理解机制，在病毒和 炎症性疾病和识别细胞和分子靶点，用于开发新的疗法。

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.