Bioengineering Tools to Resolve and Manipulate Neuroimmune Signaling

项目概要 小胶质细胞在几乎所有无法治愈的精神疾病和神经退行性疾病中都发挥着作用，但在所有 大脑中的细胞类型，它们仍然是最难研究的。培养中的人类细胞不能准确地 概括了小胶质细胞生物学，但小鼠对病原体具有明显非人类的神经免疫反应 和疾病模型。很少有方法与高反应性和组织结合的小胶质细胞兼容，阻碍了 尽一切努力来剖析他们的生物学。体内解析和操纵这些细胞的工具将加速 神经免疫研究，从基本生物功能研究到疾病机制。 在本提案中，我们改进了神经免疫研究中应用的几种技术。磁性 共振成像 (MRI) 是对从小鼠到小鼠大脑进行非侵入性研究的唯一方法之一。 人类的尺度。基于 MRI 的信号报告器提供时空分辨率和灵敏度来检测甚至 最罕见的信号和每个新传感器都可以改变我们对神经免疫信号传导的看法。基因操作在 小胶质细胞以前需要转基因，但工程改造的人类小胶质细胞前体细胞可以是异位的 植入以创建人类小胶质细胞嵌合体，携带新的传感器和疾病遗传模型。最后 将靶向基因传递到小胶质细胞目前超出了我们的能力，但在自然界中，寨卡病毒会感染 小胶质细胞，抑制炎症，并刺激自噬如此熟练，几乎一半 感染被忽视。如果这种生物活性能够被安全地精炼，它将缓解 从帕金森氏症到阿尔茨海默氏症的神经退行性疾病。这些技术结合在一起 提供全面的工具包来设计模型系统、对疾病进展进行成像和测试 人性化体内模型的治疗干预，开辟了一条通往全新之路 神经退行性疾病的治疗。

PROJECT SUMMARY Microglia have a role in nearly every incurable psychiatric and neurodegenerative disorder, but of all the cell types in the brain, they remain the least tractable to study. Human cells in culture do not accurately recapitulate microglial biology, yet mice have demonstrably non-human neuroimmune responses to pathogens and disease models. Few methods are compatible with the highly reactive and tissue bound microglia, impeding all efforts to dissect their biology. Tools to resolve and manipulate these cells in vivo would accelerate neuroimmune research, from studies of basic biological function to disease mechanisms. In this proposal we refine several technologies for application in neuroimmune research. Magnetic Resonance Imaging (MRI), is one of the only modalities for noninvasive studies of the brain from mouse to human scales. MRI based signaling reporters offer the spatiotemporal resolution and sensitivity to detect even the rarest signals and each new sensor can change our view of neuroimmune signaling. Gene manipulations in microglia formerly required transgenics, but engineered human microglial precusor cells can be ectopically implanted to create human microglial chimeras, carrying new sensors and genetic models of disease. Finally targeted gene delivery to microglia is currently beyond our capabilities, but in nature, the Zika virus infects microglia, suppresses inflammation, and stimulates autophagy so expertly that almost half of infections go unnoticed. If this bioactivity could be safely refined, it would offer relief for neurodegenerative disorders from Parkinson’s to Alzheimer's disease. Together these technologies offer a comprehensive tool kit to engineer model systems, image disease progression and test therapeutic interventions in a humanized in vivo model, creating a path towards entirely new therapies for neurodegenerative disorders.