Regulation of Monocyte Entry to the Brain During Neuroinflammation

神经炎症期间单核细胞进入大脑的调节

• 批准号: 10548813
• 负责人: Stephanie Orchanian
• 金额: $ 4.44万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548813
• 关键词: Academia; Address; Affect; Antibodies; Autoimmune Diseases; Award; Behavior Therapy; Blood; Bone Marrow; Brain; Brain Injuries; Brain region; Cell Adhesion Molecules; Cells; Central Nervous System; Central Nervous System Diseases; Communicable Diseases; Communication; Cues; Data; Development; Disease; Educational process of instructing; Encephalitis; Environment; Equilibrium; Family Felidae; Flow Cytometry; Fright; Funding; Future; Goals; Hispanic-serving Institution; Host Defense; Immune; Immune system; Immunologics; Immunology; Individual; Infection; Infiltration; Inflammation; Inflammatory; Institution; Interleukin-10; Knowledge; Laboratory Finding; Ligands; Light; Measures; Mentors; Methods; Microbiology; Microscopy; Molecular; Mus; Natural Killer Cells; Neurobiology; Neurodegenerative Disorders; Neuroimmune; Odors; Olfactory tubercle; Optics; Outcome; Parasites; Phagocytosis; Play; Population; Process; Production; Regulation; Research; Research Personnel; Research Project Grants; Resolution; Role; Scientist; Sensory; Students; Techniques; Testing; Therapeutic Intervention; Time; Toxoplasma gondii; Toxoplasmosis; Training; United States National Institutes of Health; Work; acute infection; brain health; career; chemokine; chronic infection; computational pipelines; cytokine; experimental study; foodborne; graduate student; immune cell infiltrate; improved; insight; microbiome; monocyte; motivated behavior; neural; neuroinflammation; neuropathology; novel; pathogen; prevent; programs; recruit; response; skills; symposium; therapeutic development; trafficking; training opportunity; undergraduate student

Project Summary Neuroinflammation can have both protective and detrimental outcomes in brain health, depending on the context. Immune cells that traffic to the brain may be critical for recognizing and defending against brain- infiltrating pathogens. However, excessive inflammation can lead to neuroinflammatory diseases and brain injury. Therefore, the immune system must be tightly controlled to maintain a balance that allows for host defense against infections in the brain without causing neuropathology. The long-term goal of our research is to define the factors that regulate immune cell infiltration to the central nervous system and neuroinflammation. Monocytes are inflammatory immune cells that circulate in the blood and function in host defense. They are recruited to the central nervous system (CNS) during infection with Toxoplasma gondii, a foodborne parasite that establishes chronic infection in CNS and can cause fatal encephalitis in immune-compromised individuals. Although monocytes are essential for controlling T. gondii infection in the brain, the factors that regulate their trafficking to the CNS remain poorly understood. We recently found that inflammatory monocytes preferentially infiltrate the olfactory tubercle, an interconnected brain region involved in neural processing of sensory information guiding motivated behaviors. The goal of this project is to determine the cellular and molecular basis for monocyte recruitment to the CNS and into specific brain regions. Based on strong preliminary data, we hypothesize that NK cells, adhesion molecules, chemokines, and alarmins released during brain injury contribute to monocyte recruitment to the brain. Aim 1 will determine the role of NK cells in regulating monocyte recruitment to the brain during T. gondii infection in mice. Aim 2 will determine the molecular basis for region-specific monocyte recruitment to the brain. This work is significant because an understanding of the factors regulating monocyte infiltration of the brain may enable the development of strategies to modulate neuroinflammation during CNS disease. My previous training focused on microbiology and the microbiome. The proposed research project will provide me with new training in immunology and neurobiology in the context of infectious disease and enable me to develop skills in immunological methods and high-resolution microscopy. UC Irvine is an R1 institution and Hispanic-serving institution that has demonstrated a commitment to training diverse undergraduate and graduate student populations. Also, UC Irvine was awarded funding for the NIH-BEST program, which exposes graduate students to training opportunity outside of academia and offers courses to improve the communication skills of students. The training and mentoring offered by the Sponsor and Co-Sponsor, highly collaborative and diverse scientific environment, seminars, and conferences available at UC Irvine will provide the guidance and training in research and teaching to help me develop into a successful scientist and prepare me for a future career in academic research as an independent investigator.

项目摘要 神经炎症可能在脑部健康方面具有保护性和有害结果，具体取决于 语境。传播到大脑的免疫细胞可能对于识别和防御大脑至关重要 浸润病原体。但是，过度炎症会导致神经炎症性疾病和大脑 受伤。因此，必须严格控制免疫系统，以保持平衡，以允许主机 防御大脑感染而不会引起神经病理学。我们研究的长期目标是 定义调节免疫细胞对中枢神经系统和神经炎症的因素。 单核细胞是炎性免疫细胞，在血液中循环并在宿主防御中起作用。他们是 在感染弓形虫Gondii期间，招募到中枢神经系统（CNS），这是一种食源性寄生虫 这会在中枢神经系统中建立慢性感染，并可能在免疫受损的个体中引起致命性脑炎。 尽管单核细胞对于控制大脑中的Gondii感染至关重要，但是调节其的因素 贩运中枢神经系统的理解仍然很差。我们最近发现炎症单核细胞优先 渗透嗅觉结节，这是一种与感觉神经加工有关的相互联系的大脑区域 指导动机行为的信息。该项目的目的是确定细胞和分子 单核细胞募集到中枢神经系统和特定大脑区域的基础。基于强大的初步数据 我们假设在脑损伤期间释放的NK细胞，粘附分子，趋化因子和警报 有助于对大脑的单核细胞募集。 AIM 1将确定NK细胞在调节中的作用 在小鼠t. gondii感染期间，单核细胞募集到大脑。 AIM 2将确定分子基础 用于特定区域的单核细胞募集到大脑。这项工作很重要，因为对 调节大脑单核细胞浸润的因素可能使制定策略调节 中枢神经系统疾病期间的神经炎症。我以前的培训集中在微生物学和微生物组上。 拟议的研究项目将为我提供有关免疫学和神经生物学的新培训 传染病的背景，使我能够发展免疫学方法和高分辨率的技能 显微镜。 UC Irvine是R1机构和西班牙裔服务机构，已证明 致力于培训多样化的本科和研究生人数。另外，加州大学尔湾被授予 NIH最好的计划的资金，该计划使研究生接受培训机会 学术界并提供提高学生沟通能力的课程。培训和指导 由赞助商和共同赞助商，高度协作和多样化的科学环境，研讨会和 UC Irvine提供的会议将提供研究和教学的指导和培训，以帮助我 发展成为一名成功的科学家，并为我作为独立的学术研究事业做好准备 研究者。