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.

项目总结