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，这取决于神经炎症的程度。 上下文运输到大脑的免疫细胞可能对于识别和防御大脑- 渗透病原体。然而，过度的炎症会导致神经炎性疾病和脑 损伤因此，必须严格控制免疫系统，以保持平衡，使宿主 防止大脑感染而不引起神经病理学。我们研究的长期目标是 以确定调节免疫细胞浸润到中枢神经系统和神经炎症的因素。 单核细胞是在血液中循环并在宿主防御中起作用的炎性免疫细胞。他们是 在感染弓形虫（一种食源性寄生虫）期间被招募到中枢神经系统（CNS） 在中枢神经系统中建立慢性感染，并可在免疫受损的个体中引起致命性脑炎。 虽然单核细胞是控制T。弓形虫感染在大脑中，调节他们的因素， 向中枢神经系统的贩运仍然知之甚少。我们最近发现炎症单核细胞优先 渗透到嗅结节，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 单核细胞募集到CNS和特定脑区的基础。根据强有力的初步数据， 我们假设脑损伤时NK细胞、粘附分子、趋化因子和警报素的释放 有助于单核细胞向大脑的募集。目的1将确定NK细胞在调节 T.小鼠弓形虫感染。目标2将确定分子基础 用于区域特异性单核细胞向大脑的募集。这项工作是有意义的，因为了解 调节脑单核细胞浸润的因素可能有助于开发调节脑单核细胞浸润的策略。 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。 拟议的研究项目将为我提供免疫学和神经生物学方面的新培训， 感染性疾病的背景下，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个R1机构和西班牙裔服务机构，已经证明了 致力于培养多样化的本科生和研究生群体。此外，加州大学欧文分校被授予 为NIH-BEST计划提供资金，该计划使研究生获得在 该中心致力于促进学术界的交流，并提供课程以提高学生的沟通技巧。培训和辅导 由申办者和联合申办者提供高度协作和多元化的科学环境、研讨会和 在加州大学欧文分校提供的会议将提供指导和培训的研究和教学，以帮助我 发展成为一个成功的科学家，并为我未来的学术研究生涯做好准备，作为一个独立的 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.