Targeting IDO in SARS-CoV2-induced Alzheimer's Disease progression

在 SARS-CoV2 诱导的阿尔茨海默病进展中靶向 IDO

基本信息

批准号：
10670498
负责人：
Irma Cisneros
金额：
$ 40万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670498
关键词：
2019-nCoV Address Advanced Development Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s neuropathogenesis American Amyloid beta-Protein Animal Disease Models Area Automobile Driving Behavioral Biological Factors Biological Markers Biology Blood Brain COVID-19 COVID-19 impact COVID-19 patient Cause of Death Cells Central Nervous System Infections Cerebrospinal Fluid Characteristics Cognitive Communicable Diseases Confusion Data Delirium Deposition Development Disease Progression Encephalitis Environmental Risk Factor Enzymes Epidemiology Etiology Future Goals HIV Health Histologic Hospitalization Human Immune Immune response Immunity Immunologic Markers Impaired cognition Individual Infection Infiltration Inflammation Inflammatory Inflammatory Response Ingestion Inherited Kynurenic Acid Kynurenine Learning Link Lymphocyte Measures Mediating Memory Memory impairment Metabolic Mus Nerve Degeneration Neuraxis Neurocognitive Deficit Neurodegenerative Disorders Neurologic Neuropathogenesis Onset of illness Pathology Pathway interactions Patients Peripheral Physiological Process Production Public Health Quinolinic Acid Research Risk Risk Factors Route SARS-CoV-2 infection SARS-CoV-2 inhibitor Severities Severity of illness Signal Pathway Signal Transduction Testing Tg2576 Transgenic Organisms Tryptophan Tryptophan 2,3 Dioxygenase United States Virus Virus Diseases Wild Type Mouse base burden of illness cognitive process cytokine release syndrome dysphoria experience functional status global health insight neurobehavior neuroinflammation neurologic sequelae of COVID-19 neuropathology neuropsychiatry pathogen payment post SARS-CoV-2 infection pre-clinical response tau Proteins therapeutic development translational study

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) is a national health crisis, affecting many Americans with total annual payments projected to be more than $1 trillion by 2050. The risk for Alzheimer’s disease (AD) is an interaction between inherited and environmental risk factors that, with age, drives pathology resulting in neurodegeneration and disease onset. Increasing epidemiological evidence indicates that ~80% of individuals infected with SARS-CoV2, and who develop Covid-19, experience neurological sequelae characterized by common etiological factors of Alzheimer’s disease, including cognitive and neuropsychiatric deficits. Therefore, there is a strong possibility in SARS-CoV2 causation of neurological conditions, such as Alzheimer’s disease, based on the biology and host immune responses to the virus. Biological factors intertwined with the overactivity of the CNS inflammatory response during Covid-19, impact the functional status of the CNS. For example, the bidirectional relationship between CNS inflammation and dysregulation of the kynurenine (KYN) pathway (KP) and its metabolites, such as kynurenic acid (KYNA) and quinolinic acid (QUIN), are found in the blood and cerebrospinal fluid of AD patients; and levels are correlated to severity of neurological and cognitive impairments associated with viral infections such as HIV. Importantly, disruption and dysregulation of KP metabolites in Covid-19 patients is correlated to disease severity and triggered by inflammation-induced indoleamine 2,3-dioxygenase (IDO). This indicates that dysregulation of critical KP metabolites and CNS inflammation by SARs-CoV2 may underlie maladaptive changes in the CNS that exacerbate the development of AD. Therefore, it is critical to elucidate the interplay between SARS-CoV2-induced KP dysregulation and CNS inflammation during Covid-19 and the impact on AD disease progression and neuropathogenesis. The long-term goal of this proposal is to investigate the infectious disease risk factors and mechanisms underlying the neuropathogenesis of AD during the progression of SARS-CoV2 neurological sequelae. Using mouse-adapted SARS-CoV2, we will address our overall objective: to delineate KP dysregulation during SARS-CoV2 CNS infection and progression of Alzheimer’s neuropathology and neurocognitive decline correlative to CNS immune responses and encephalitic infection. The central hypothesis is that SARS-CoV2 is a significant risk factor for the onset and severity of AD, by triggering IDO activity thereby dysregulating KP metabolites in the periphery and CNS and exacerbating the subsequent cytokine storm to exacerbate AD neuropathology. To address this hypothesis, we will 1) distinguish AD-related cognitive decline exacerbated following SARS-CoV2 infection, 2) delineate SARS- CoV2 neuropathology, disease burden, and dual activation of host immunity and KP signaling in AD, and 3) elucidate specific IDO contributions in SARs-CoV2-mediated exacerbation of AD onset and severity. This proposal will provide an immune-KP focused approach to identify SARS-CoV2 on the impact of neurodegenerative processes in AD.

项目概要/摘要阿尔茨海默病 (AD) 是一场全国性的健康危机，影响着许多美国人的年付款总额预计到 2050 年将超过 1 万亿美元。阿尔茨海默病 (AD) 的风险是以下因素之间的相互作用：随着年龄的增长，遗传和环境风险因素会驱动病理学，导致神经退行性变和越来越多的流行病学证据表明，约 80% 的人感染了 SARS-CoV2，患有 Covid-19 的人会经历神经系统后遗症，其常见病因为因此，阿尔茨海默病，包括认知和神经精神缺陷，很有可能。基于生物学和宿主的 SARS-CoV2 导致神经系统疾病（例如阿尔茨海默病）的原因对病毒的免疫反应与中枢神经系统的过度活跃交织在一起。 Covid-19 期间的炎症反应会影响中枢神经系统的功能状态，例如双向。中枢神经系统炎症与犬尿氨酸 (KYN) 通路 (KP) 失调之间的关系及其代谢物，如犬尿酸 (KYNA) 和喹啉酸 (QUIN)，存在于血液和脑脊液中 AD 患者的体液水平与神经系统和认知障碍的严重程度相关重要的是，Covid-19 患者中 KP 代谢物的破坏和失调。与疾病严重程度相关，并由炎症诱导的吲哚胺 2,3-双加氧酶 (IDO) 触发。表明 SARs-CoV2 对关键 KP 代谢物和中枢神经系统炎症的失调可能是其原因中枢神经系统的适应不良变化会加剧 AD 的发展，因此，阐明这一变化至关重要。 Covid-19 期间 SARS-CoV2 诱导的 KP 失调与中枢神经系统炎症之间的相互作用对 AD 疾病进展和神经发病机制的影响该提案的长期目标是研究传染病的危险因素和神经发病机制我们将使用小鼠适应的 SARS-CoV2 来研究 AD 在 SARS-CoV2 神经系统后遗症进展过程中的作用。解决我们的总体目标：描述 SARS-CoV2 CNS 感染和进展期间 KP 失调阿尔茨海默病的神经病理学和与中枢神经系统免疫反应相关的神经认知能力下降中心假设是 SARS-CoV2 是脑炎发病和发生的重要危险因素。 AD 的严重程度，通过触发 IDO 活性从而失调外周和 CNS 中的 KP 代谢物，加剧随后的细胞因子风暴会加剧 AD 神经病理学为了解决这一假设。将 1) 区分 SARS-CoV2 感染后与 AD 相关的认知能力下降，2) 描述 SARS- AD 中的 CoV2 神经病理学、疾病负担以及宿主免疫和 KP 信号传导的双重激活，以及 3) 阐明 IDO 在 SARs-CoV2 介导的 AD 发作和严重程度恶化中的具体作用。该提案将提供一种以免疫 KP 为重点的方法来识别 SARS-CoV2 对 AD 中的神经退行性过程。