Cognate microglia-neuron interaction and its role in inflammation

描述(由申请人提供) 摘要：该提案解决了神经元对小胶质细胞调节这一鲜为人知的问题。小胶质细胞的激活是大脑稳态的核心，小胶质细胞参与神经元监测以及对病原体的免疫防御。我们假设，这种塑造健康和疾病中大脑功能的细胞动力学需要小胶质细胞调整到不同大脑区域高度专业化的神经元的特定功能。我们的计划包括空间小胶质细胞多样性及其发育机制的研究。利用小鼠遗传学的方法，我们将获得小胶质细胞对其神经元环境的“模仿”的可能性，以及它在小胶质细胞介导的炎症反应调节中的作用。在一系列补充实验中，我们将讨论神经元活动对小胶质细胞功能和炎症基因激活的作用。我们的建议对于理解小胶质细胞-神经元相互作用在调节大脑炎症反应中的作用具有深远的影响。这项拟议的工作在神经科学、细胞分化、谱系可塑性和先天免疫等不同领域之间建立了深刻的联系。因此，它将产生一个新的框架来理解小胶质细胞与神经元的相互作用，对于我们如何理解和控制小胶质细胞的功能，特别是在神经退行性疾病的背景下，具有重要的意义。 公共卫生相关性：这项拟议的研究解决了小胶质细胞-神经元相互作用的一个鲜为人知的机制，以及它在小胶质细胞介导的炎症反应中的作用。除了基本的基础科学意义之外，我们的工作有可能对研究神经退行性变的机制及其治疗进行革命性的策略研究。我们的发现将为开发治疗炎症相关神经退行性疾病的新方法提供基础，如帕金森氏症、亨廷顿氏症和阿尔茨海默病。

DESCRIPTION (Provided by the applicant) Abstract: The proposal addresses the poorly explored problem of microglia regulation by neurons. Activation of microglia is at the core of brain homeostasis, where microglia cells are involved in neuronal surveillance, as well as in immune defense against pathogens. We hypothesize that such cellular dynamics that shape brain function in health and disease require microglia tuning to the specific functions of highly specialized neurons in distinct brain areas. Our plans include investigations of spatial microglia diversity and its developmental mechanisms. Using methods of mouse genetics, we will access the possibility of microglia ""mimicry"" of its neuronal environment and its role in the regulation of microglia-mediated inflammatory response. In a complementary set of experiments, we will address the role of neuronal activity on microglia function and inflammatory gene activation. Our proposal has far reaching consequences for understanding of the role of microglia-neuron interaction in the regulation of inflammatory responses in the brain. The proposed work establishes deep connections between the disparate fields of neuroscience, cell differentiation, lineage plasticity and innate immunity. Thus, it will generate a new framework for understanding of the microglia-neuron interaction with fundamental implications for how we understand and control microglia function, especially within the context of neurodegenerative diseases. Public Health Relevance: The proposed research addresses a poorly understood mechanism of microglia -neuron interaction and its role in microglia-mediated inflammatory responses. Beyond the fundamental basic science implications, our work has the potential of revolutionizing strategies to study the mechanisms of neurodegeneration and its treatment. Our findings will provide a foundation for the development of new approaches for treatment of inflammation associated neurodegenerative disease such as Parkinson's, Huntington's, and Alzheimer disease.