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：
10397683
负责人：
Robyn S Klein
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 2029-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397683
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 Inflammasome Laboratories Learning Magnetic Resonance Imaging Maintenance Mediating Mediator of activation protein Memory Memory Disorders Methods Microglia Modality Modeling Molecular Mononuclear Mus Myeloid Cells National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous system structure Neurocognitive Deficit Neurodegenerative Disorders Neurons Neurosciences Optics Pathologic Pathway interactions Patient Monitoring Patients Persons Pharmacology 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 memory cell T-Lymphocyte Therapeutic Virus Virus Diseases West Nile virus ZIKA 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 programs repaired response stem cell fate tool vector-borne infection virology

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 Inflammasome Laboratories Learning Magnetic Resonance Imaging Maintenance Mediating Mediator of activation protein Memory Memory Disorders Methods Microglia Modality Modeling Molecular Mononuclear Mus Myeloid Cells National Institute of Neurological Disorders and Stroke Nerve Degeneration Nervous system structure Neurocognitive Deficit Neurodegenerative Disorders Neurons Neurosciences Optics Pathologic Pathway interactions Patient Monitoring Patients Persons Pharmacology 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 memory cell T-Lymphocyte Therapeutic Virus Virus Diseases West Nile virus ZIKA 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 programs repaired response stem cell fate tool vector-borne infection virology

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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.

项目摘要/摘要现在，病毒感染被认为是进行性病理遗忘的疾病的危险因素，支持一种新的神经免疫学范式，从而使先天免疫分子起作用各种普通CNS功能的调节剂在宿主病原体期间诱导神经退行性疾病回答。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鉴定疾病的新机制至关重要，发现神经影像学工具和治疗疗法，用于多种记忆障碍疾病。在我的实验室我们对中枢神经系统浸润的单核作用的意外，范式转移发现小胶质介导的突触消除，成年神经发生破坏和神经毒性的产生的细胞星形胶质细胞使用新型的脑源性黄病毒，西尼罗河（WNV）和Zika的恢复模型（zikv）病毒。我们确定经典补体蛋白和细胞因子受体信号传导是新的分子调节突触消除，神经干细胞（NSC）命运的介体，神经元 - 神经元和小胶质细胞在调节记忆形成和维护的皮质结构内的星形胶质细胞串扰。我们也有开始利用新型的神经影像模式来开发可用于预测和的生物标志物监测有记忆障碍风险的患者。我们的目的是了解引起改变的机制在恢复后神经元网络中断的突触连接和修复方法中来自病毒感染。我们的研究计划侧重于与角色和监管有关的三个广泛领域先天免疫分子参与空间学习，使用新颖的鼠类认知后认知模型功能障碍。首先，使用遗传，药理学和PET-MRI，我们将识别并定义分子 T细胞与小胶质细胞或神经元之间的相互作用，这些神经元可以驱动居民的生成和维护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筛选通过细胞因子或趋化因子受体的细胞特异性缺失靶向基因和途径，或抑制或增强途径的药物的给药。我们还将开发使用的诊断工具 ABSL3 PET-MRI。其次，我们将定义在恢复背景下如何相互作用的小胶质细胞-ASTROCYTE-NSC 从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球和有条件的基因靶向描述细胞因子在调节星形胶质细胞炎症体激活和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。我们还将定义直接的先天免疫机制并在急性病毒感染期间维持天气生成症，并使用P2X7R的PET-MRI检测反应性星形胶质细胞的标记。最后，将利用记者小鼠/命运映射，骨髓嵌合体和 scrnaseq描绘髓样细胞在神经毒性星形胶质细胞产生中的细胞因子介导的作用在WNND恢复期间。第三，我们将研究病毒感染后触发的先天免疫机制负面影响皮层连通性，并确定是否可以使用神经影像来预测和遵循这个过程。具体而言，我们将将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定义对皮质连通性产生负面影响的机制。我们的研究计划将在突触，T细胞的分子神经免疫性调节中定义新概念以及神经胶质相互作用，为整个神经系统中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和其他记忆障碍的理解。