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Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS

研究计划奖（R35 临床试验可选）- Robyn Klein NINDS 博士

基本信息

批准号：
10617681
负责人：
Matthew D Cain
金额：
$ 118.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617681
关键词：
2019-nCoV Acute Alzheimer&apos s Disease Area Astrocytes Award Binding Biological Markers Bone Marrow Calcium Cell Communication Cells Central Nervous System Viral Diseases Chimera organism Clinical Trials Cognitive Complement Cytokine Receptors Dementia Detection Development Diagnostic Disease Exhibits Flavivirus Gene Targeting Generations Genes Genetic Hemoglobin Image Immune Immunology Impaired cognition Infiltration Inflammasome Laboratories Learning Magnetic Resonance Imaging Maintenance Maps Mediating Mediator Memory Memory Disorders Methods Microglia Modality Modeling Molecular Mononuclear Mus Myeloid Cells National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous System Neurocognitive Deficit Neurodegenerative Disorders Neuroimmune Neurons Neurosciences Optics Pathologic Pathway interactions Patient Monitoring Patients Persons Positron-Emission Tomography Process Progressive Disease RNA Viruses Receptor Signaling Recovery Regulation Reporter Research Risk Risk Factors Role Signal Transduction Structure Survivors Synapses Syndrome T-Lymphocyte Therapeutic Virus Virus Diseases West Nile virus Zika Virus adult neurogenesis cell type chemokine receptor cytokine diagnostic tool forgetting genetic approach in vivo innate immune mechanisms mouse model multidisciplinary nerve stem cell neuroimaging neuroimmunology neurotoxic neurotropic novel pathogen pharmacologic programs repaired response stem cell fate tissue resident memory T cell tool transmission process vector-borne infection virology

项目摘要

PROJECT SUMMARY/ABSTRACT Viral infections are now recognized as risk factors for diseases of progressive pathological forgetting, supporting a new paradigm in neuroimmunology whereby innate immune molecules that function as modulators of a variety of normal CNS functions induce neurodegenerative diseases during host-pathogen responses. Studying virus-mediated cognitive dysfunction through the multidisciplinary prism of immunology, neuroscience, and virology is critical for the identification of novel mechanisms of disease, discovery of neuroimaging tools and therapeutic treatments for a wide range of diseases of memory disorder. In my laboratory we made unanticipated, paradigm-shifting discoveries of the roles of CNS infiltrating mononuclear cells in microglial-mediated synapse elimination, disrupted adult neurogenesis, and generation of neurotoxic astrocytes using novel models of recovery from encephalitogenic flaviviruses, West Nile (WNV) and Zika (ZIKV) viruses. We identified classical complement proteins and cytokine receptor signaling as novel molecular mediators that regulate synapse elimination, neural stem cell (NSC) fates, neuron-microglia and microglia- astrocyte crosstalk within cortical structures that regulate memory formation and maintenance. We have also begun leveraging novel neuroimaging modalities to develop biomarkers that may be used to predict and monitor patients at risk for memory disorders. Our aim is to understand the mechanisms that induce alterations in synaptic connections and methods of repair that contribute to disruption of neuronal networks after recovery from viral infections. Our research program focuses on three broad areas related to the roles and regulation of innate immune molecules involved in spatial learning using novel murine models of post-infectious cognitive dysfunction. First, using genetic, pharmacologic and PET-MRI, we will identify and define molecular interactions between T cells and microglia or neurons that drive the generation and maintenance of resident memory T cells that promote cognitive dysfunction. We will use scRNAseq under BSL3 conditions to screen for genes and pathways to be targeted via cell-specific deletion of cytokine or chemokine receptors, or administration of agents that inhibit or enhance pathways. We will also develop diagnostic tools that employ ABSL3 PET-MRI. Second, we will define how microglia-astrocyte-NSC interactions in the context of recovery from CNS viral infections limit repair and recovery. We will use global and conditional gene targeting in mice to delineate the in vivo roles of cytokines in neural cell types that regulate astrocyte inflammasome activation and its relationship to neuronal and synapse recovery. We will also define innate immune mechanisms that direct and maintain astrogenosis during acute viral infection and recovery using PET-MRI detection of P2X7R, a marker of reactive astrocytes. Finally, will utilize reporter mice/fate mapping, bone marrow chimeras and scRNAseq to delineate the cytokine-mediated roles of myeloid cells in the generation of neurotoxic astrocytes during WNND recovery. Third, we will examine innate immune mechanisms triggered after viral infections that negatively impact cortical connectivity and determine whether neuroimaging can be used to predict and follow this process. Specifically, we will combine genetic approaches with functional optical intrinsic signal imaging of hemoglobin and calcium dynamics to define mechanisms that negatively impact cortical connectivity. Our research program will define new concepts in the molecular neuroimmunological regulation of synapses, T cell and glial interactions, inform studies of related processes throughout the nervous systems, and will likely enhance our understanding of neurodegenerative and other disorders of memory.

项目概要/摘要病毒感染现在被认为是进行性病理性遗忘疾病的危险因素，支持神经免疫学的新范式，其中先天免疫分子发挥作用多种正常中枢神经系统功能的调节剂在宿主-病原体过程中诱发神经退行性疾病回应。通过免疫学的多学科棱镜研究病毒介导的认知功能障碍，神经科学和病毒学对于识别疾病的新机制、发现针对多种记忆障碍疾病的神经影像工具和治疗方法。在我的我们在实验室中对中枢神经系统浸润单核细胞的作用做出了意想不到的、范式转变的发现小胶质细胞介导的突触消除、破坏的成体神经发生和神经毒性物质的产生使用从致脑炎黄病毒、西尼罗河病毒 (WNV) 和寨卡病毒中恢复的新型星形胶质细胞模型（ZIKV）病毒。我们将经典补体蛋白和细胞因子受体信号传导确定为新型分子调节突触消除、神经干细胞（NSC）命运、神经元小胶质细胞和小胶质细胞的介质皮质结构内的星形胶质细胞串扰调节记忆的形成和维持。我们还有开始利用新的神经成像模式来开发可用于预测和预测的生物标志物监测有记忆障碍风险的患者。我们的目标是了解引起改变的机制突触连接和修复方法有助于恢复后神经元网络的破坏来自病毒感染。我们的研究计划侧重于与角色和监管相关的三个广泛领域使用感染后认知的新型小鼠模型参与空间学习的先天免疫分子功能障碍。首先，利用遗传学、药理学和 PET-MRI，我们将识别和定义分子 T 细胞与小胶质细胞或神经元之间的相互作用，驱动常驻细胞的生成和维持促进认知功能障碍的记忆 T 细胞。我们将在BSL3条件下使用scRNAseq来筛选通过细胞特异性删除细胞因子或趋化因子受体来靶向的基因和途径，或施用抑制或增强途径的药物。我们还将开发诊断工具 ABSL3 PET-MRI。其次，我们将定义小胶质细胞-星形胶质细胞-NSC 在恢复过程中如何相互作用中枢神经系统病毒感染限制了修复和恢复。我们将在小鼠中使用全局和条件基因靶向描述细胞因子在调节星形胶质细胞炎症小体激活的神经细胞类型中的体内作用它与神经元和突触恢复的关系。我们还将定义指导先天免疫机制并使用 PET-MRI 检测 P2X7R（一种反应性星形胶质细胞的标记。最后，将利用报告小鼠/命运图谱、骨髓嵌合体和 scRNAseq 描述骨髓细胞在神经毒性星形胶质细胞生成中细胞因子介导的作用在 WNND 恢复期间。第三，我们将检查病毒感染后触发的先天免疫机制对皮质连接产生负面影响，并确定神经影像是否可用于预测和跟踪这个过程。具体来说，我们将把遗传方法与功能性光学固有信号成像相结合血红蛋白和钙动力学来定义对皮质连接产生负面影响的机制。我们的研究计划将定义突触、T 细胞的分子神经免疫调节的新概念和神经胶质细胞的相互作用，为整个神经系统相关过程的研究提供信息，并且很可能增强我们对神经退行性疾病和其他记忆障碍的理解。