Regulation of Monocyte Entry to the Brain During Neuroinflammation

项目摘要 神经炎症对大脑健康既有保护作用，也有有害作用，这取决于 背景。进入大脑的免疫细胞可能是识别和防御大脑的关键- 渗入病原体。然而，过度的炎症会导致神经炎症性疾病和大脑 受伤。因此，免疫系统必须受到严格控制，以维持允许宿主 在不引起神经病理的情况下防御大脑感染。我们研究的长期目标是 明确调节免疫细胞向中枢神经系统的渗透和神经炎症的因素。 单核细胞是一种炎性免疫细胞，在血液中循环，发挥宿主防御的功能。他们是 在感染食源性寄生虫弓形虫时被招募到中枢神经系统(CNS) 这会在中枢神经系统建立慢性感染，并可能在免疫受损的人中导致致命的脑炎。 尽管单核细胞对控制脑内弓形虫感染是必不可少的，但调节其感染的因素 贩运到中南欧的人仍然知之甚少。我们最近发现炎性单核细胞优先 侵入嗅结节，这是一个相互连接的大脑区域，参与感觉的神经处理 引导动机行为的信息。这个项目的目标是确定细胞和分子 单核细胞向中枢神经系统和特定脑区募集的基础。基于强劲的初步数据， 我们假设NK细胞、黏附分子、趋化因子和警素在脑损伤过程中释放。 有助于单核细胞向大脑募集。目标1将确定NK细胞在调节 弓形虫感染小鼠时单核细胞向脑内募集。目标2将确定分子基础 使特定区域的单核细胞重新聚集到大脑中。这项工作意义重大，因为对 调节脑内单核细胞渗透的因素可能使调节策略的发展成为可能 中枢神经系统疾病中的神经炎症。我之前的培训重点是微生物学和微生物组。 拟议的研究项目将为我提供新的免疫学和神经生物学方面的培训 传染病的背景，并使我能够发展免疫学方法和高分辨率的技能 显微镜。加州大学欧文分校是一家R1机构和服务于西班牙裔的机构，它已经展示了 致力于培养不同的本科生和研究生群体。此外，加州大学欧文分校还获得了 为NIH-BEST项目提供资金，该项目为研究生提供了在国外培训的机会 并提供课程，以提高学生的沟通技能。培训和指导 由赞助商和共同赞助商提供高度协作和多样化的科学环境、研讨会和 加州大学欧文分校的会议将提供研究和教学方面的指导和培训，以帮助我 成长为一名成功的科学家，并为我未来作为独立的学术研究人员的职业生涯做好准备 调查员。

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.