Machine Learning Augmented Discovery of AAV Capsids for Cell Type Specific Access into Human Neurons and Glia

机器学习增强了 AAV 衣壳的发现，用于特定细胞类型进入人类神经元和神经胶质细胞

• 批准号: 10512547
• 负责人: Tomasz Nowakowski
• 金额: $ 289.35万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512547
• 关键词: Address; Adult; Area; Atlases; BRAIN initiative; Biomedical Engineering; Brain; Brain region; Capsid; Cell Nucleus; Cell physiology; Cells; Censuses; Cerebral cortex; Collaborations; Data; Development; Directed Molecular Evolution; Emerging Technologies; Engineering; Enhancers; Gene Delivery; Gene Expression; Genetic Enhancer Element; Genomics; Goals; Grant; Hippocampus (Brain); Human; In Vitro; Infrastructure; Injections; Interneurons; Intravenous; Knowledge; Label; Libraries; Light; Machine Learning; Maps; Measures; Methodology; Methods; Molecular; Monkeys; Mus; Neurobiology; Neuroglia; Neurons; Neurosciences; Physiological; Pilot Projects; Population; Primates; Process; Property; Prosencephalon; Regulatory Element; Reporting; Resolution; Resources; Role; Slice; Specificity; Structure; Synapses; Technology; Testing; Time; Tissues; Validation; Variant; Viral; Viral Genes; Viral Vector; Virus; Work; adeno-associated viral vector; brain cell; brain tissue; cell type; epigenomics; experimental study; frontal lobe; genetic resource; head-to-head comparison; human tissue; in vivo; machine learning model; next generation sequencing; nonhuman primate; novel; optogenetics; patch sequencing; single cell analysis; spatiotemporal; tool; tool development; transcriptomics; translational study; vector

Project Summary The human brain contains an astonishing diversity of neuronal and glial cell types distributed across dozens of functional areas. Single cell genomics resources generated by the BRAIN Initiative Cell Census have offered a wealth of reference knowledge about this diversity, including cell types present in human and non-human primate brain. However, we currently lack scalable technologies to genetically access these specific cell types, which will be necessary to advance our understanding of their function. By leveraging our expertise in viral engineering, single cell analysis, machine learning, and non-human and human primate neuroscience, we propose to develop a scalable toolkit for accessing distinct cell types in the human brain. Specifically, our U01 application will develop novel adeno-associated viral (AAV) vectors for cell type-specific gene delivery using machine learning augmented engineering of capsid libraries. In this pilot grant, we seek to demonstrate the potential of our approach to support the development of a comprehensive Armamentarium for brain cell types that would enable functional and translational studies across a broad range of applications. In particular, we will apply this methodology to develop AAV vectors for cell types in the human forebrain, including the hippocampus. Our tools will be openly disseminated after validation for specificity using molecular and physiological metrics, and mapped onto existing single cell genomics resources from the same brain regions generated by the BRAIN Initiative Cell Census projects. If successful, our project will establish a scalable infrastructure for addressing and functionally investigating in principle any tissue or cell type in the non-human or human primate brain.

项目摘要 人类大脑包含分布在数十个神经元和神经胶质细胞类型的惊人多样性。 功能区。由BRAIN Initiative Cell Census产生的单细胞基因组学资源提供了一个 关于这种多样性的丰富参考知识，包括人类和非人类灵长类动物中存在的细胞类型 个脑袋然而，我们目前缺乏可扩展的技术来遗传访问这些特定的细胞类型，这将 这是必要的，以促进我们对它们的功能的理解。 通过利用我们在病毒工程、单细胞分析、机器学习和非人类和 人类灵长类神经科学，我们建议开发一个可扩展的工具包，用于访问不同的细胞类型， 人脑具体而言，我们的U01申请将开发用于细胞增殖的新型腺相关病毒（AAV）载体。 使用衣壳文库的机器学习增强工程的类型特异性基因递送。在这个试点项目中， 我们寻求展示我们的方法的潜力，以支持发展一个全面的 用于脑细胞类型的设备，可以进行广泛的功能和转化研究 的应用程序。 特别地，我们将应用该方法来开发用于人前脑中的细胞类型的AAV载体， 包括海马体我们的工具将在使用分子生物学方法验证特异性后公开传播。 和生理指标，并映射到现有的单细胞基因组资源从相同的大脑区域 由BRAIN Initiative Cell Census项目产生。 如果成功，我们的项目将建立一个可扩展的基础设施，用于解决 原则上，非人类或人类灵长类动物大脑中的任何组织或细胞类型。