Bioengineering Tools to Resolve and Manipulate Neuroimmune Signaling

解决和操纵神经免疫信号传导的生物工程工具

• 批准号: 10687761
• 负责人: Benjamin B Bartelle
• 金额: $ 133.65万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687761
• 关键词: Acceleration; Alzheimer' s Disease; Autophagocytosis; Binding; Biological Models; Biological Process; Biology; Biomedical Engineering; Brain; Cells; Chimera organism; Disease; Disease Progression; Disease model; Engineering; Gene Delivery; Genes; Genetic Models; Human; Human Engineering; Image; Implant; Infection; Inflammation; Magnetic Resonance Imaging; Mental disorders; Methods; Microglia; Modality; Mus; Nature; Neurodegenerative Disorders; Neuroimmune; Parkinson Disease; Pathology; Reporter; Research; Resolution; Role; Signal Transduction; Technology; Therapeutic Intervention; Tissues; Viral Vector; Zika Virus; cell type; genetic manipulation; humanized mouse; implantation; in vivo; in vivo Model; neuroinflammation; non-invasive imaging; novel; novel therapeutics; pathogen; response; sensor; spatiotemporal; therapeutic evaluation; tool

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.

项目摘要 小胶质细胞在几乎所有无法治愈的精神病和神经退行性疾病中都有作用，但在所有这些疾病中， 大脑中的细胞类型，它们仍然是最不容易研究的。培养中的人类细胞不能准确地 概括小胶质细胞生物学，但小鼠对病原体具有明显的非人类神经免疫反应 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相容，阻碍了细胞的增殖。 尽一切努力剖析它们的生物学。在体内分解和操纵这些细胞的工具将加速 神经免疫研究，从基本的生物学功能到疾病机制的研究。 在本提案中，我们改进了几种应用于神经免疫研究的技术。磁 核磁共振成像（MRI）是唯一一种用于从小鼠到大鼠脑的非侵入性研究的模式之一。 人的尺度基于MRI的信号报告子提供了时空分辨率和灵敏度，以检测甚至 最罕见的信号和每一个新的传感器都可以改变我们对神经免疫信号的看法。Gene manipulations in 小胶质细胞以前需要转基因，但工程化的人类小胶质细胞前体细胞可以异位 植入以创造人类小胶质细胞嵌合体，携带新的传感器和疾病的遗传模型。最后 目前，向小胶质细胞靶向基因递送超出了我们的能力，但在自然界中，寨卡病毒感染 小胶质细胞，抑制炎症，并刺激自噬如此熟练，几乎一半的 感染不会被注意到如果这种生物活性可以安全地提炼，它将为 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 提供一个全面的工具包，以工程模型系统，图像疾病进展和测试 在人源化的体内模型中进行治疗干预，创造了一条通往全新的 神经退行性疾病的治疗。