Engineered AAV Identification, Validation, and Dissemination Pipeline for Brain Cell Type-Specific Manipulation Across Species

项目概要： 这个团队的倡议将为广泛的神经科学界提供一种细胞类型特异性的腺病毒， 相关病毒（AAV）医疗设备，用于容易和非侵入性地实施新的和 用于啮齿动物神经系统解剖和功能分析的新兴分子工具， 非人类灵长类动物和人类类器官。 我们将表征工程AAV衣壳的细胞类型和大脑区域特异性基因传递 (Aim 1）。我们将把这些衣壳与最近优化和新开发的传感器货物配对 和效应器，主要是由大脑倡议，并验证其功能效用大- 跨物种大脑功能的规模监测和操纵（目标2）。最后我们将 建立一个AAV电子资源门户，将所有这些工具编目并分发给 更广泛的研究社区（目标3）。 该提案有望验证一系列广泛的工程化系统性AAV， 分子定义的神经元细胞类型，用于递送脑相关的货物和功能 对不同物种脑细胞的研究。为了最大限度地利用这些工具， 神经科学界，我们将参与广泛的合作和传播。基础上 在三叶草中心的AAV生产设施建立网络，我们将促进广泛的 通过协商和合作采用系统的自动驾驶飞机，包括提供费用- 免费样品AAV制备。我们将探索AAV生产的方法创新， 同时催化工程化衣壳的早期采用和验证 通过创建用于分发试剂的电子AAV资源， 和最佳实践，包含编目的AAV大脑图谱和数据重新捕获门户， 持续的众包验证 在本提案的生命周期内建立的专业知识和基础设施将构成 AAV BRAIN SENSUS（安全有效的神经调节剂）长期综合中心 和跨物种的传感器利用率），这将为神经科学工具验证打开新的大门 和传播。

PROJECT SUMMARY: This team initiative will provide the broad neuroscience community with a cell type-specific adeno- associated virus (AAV) armamentarium for easy and non-invasive implementation of novel and emerging molecular tools for anatomical and functional analysis of the nervous system in rodents, non-human primates, and human organoids. We will characterize engineered AAV capsids for cell type- and brain region-specific gene delivery (Aim 1). We will pair these capsids with cargos of recently optimized and newly developed sensors and effectors, largely enabled by the BRAIN Initiative, and validate their functional utility for large- scale monitoring and manipulation of brain function across species (Aim 2). Finally, we will establish an electronic AAV resource portal to catalogue and disseminate all of these tools to the broader research community (Aim 3). This proposal promises to validate a broad array of engineered systemic AAVs with access to molecularly defined neuronal cell types for delivery of BRAIN-relevant cargo and functional interrogation of brain cells across species. To maximize the utility of these tools to the neuroscientific community, we will engage in broad collaboration and dissemination. Building on the CLOVER Center’s established network of AAV production facilities, we will facilitate the broad adoption of systemic AAVs through consultation and collaboration, including provision of cost- free sample AAV preps. We will explore methodological innovations in AAV production and administration while catalyzing the early-stage adoption and validation of engineered capsids identified in this proposal by creating an electronic AAV resource for dissemination of reagents and best practices, containing catalogued AAV brain atlases and a data re-capture portal for continuous, crowd-sourced validation. The expertise and infrastructure built over the life of this proposal will form the foundation of a long-term comprehensive center for AAV BRAIN SENSUS (Safe and Effective Neuromodulator and Sensor Utilization across Species) that will open new doors for neuroscience tool validation and dissemination.