Towards an integrated analytics solution to creating a spatially-resolved single-cell multi-omics brain atlas

项目总结 神经系统的维持和功能取决于细胞之间的相互作用。 神经元和非神经元细胞群，通过物理结合细胞膜表面而发生 或分泌蛋白质，触发激活细胞型基因调控程序的信号级联反应。这个 细胞-细胞互动体对生理上改变的微环境进行反应和调节 大脑发育和衰老等过程，或在不同疾病的发生和发展期间 神经精神障碍。尽管在解剖细胞异质性方面取得了很大进展 通过单细胞转录组和表观基因组图谱，破译基因调控的空间图谱 调节人类神经元和非神经元细胞群之间细胞间相互作用的程序 神经系统缺失。 已经开发了新的技术来生成转录组规模的基因表达谱 在原始组织环境中具有高空间分辨率，从而大大方便了结构 组织微环境的表征以及细胞-细胞相互作用的机制研究。 空间转录组学技术越来越多地被NIH脑研究中心使用 创新神经技术(脑)倡议，并被视为细胞图谱的重要组成部分 建设努力。空间转录组和多组体数据的综合分析在 构建一个完整的空间分辨率脑图谱。然而，系统化仍是一个挑战。 分析、比较和集成不同组生成的数据，部分原因是差异很大 在技术平台和数据分析管道方面。 在以前的工作中，我们的实验室已经将Giotto开发为一个强大的空间综合工具箱 转录组分析。在这个项目中，我们建议使用Giotto作为基础来创建基于云的 软件平台，并进一步开发新的管道，促进协调和整合Brain倡议 数据集。具体目标是：1.开发基于云的空间协调软件平台 转录组数据分析和可视化；2.阐明介导细胞- 通过综合空间多组学分析大脑中的细胞相互作用；以及3.创建基准 空间转录学技术和数据分析管道的客观评估系统。已被占用 总之，我们提出的研究将产生强大的计算工具，不仅有助于大脑 首创研究人员构建空间分辨脑图谱，同时也使广大社区能够 在自己的研究中高效利用大脑倡议产生的丰富资源。

PROJECT SUMMARY The maintenance and function of the nervous system depends on cell-cell interactions among neuronal and non-neuronal cell populations, which occur through physically binding cell membrane surface or secreted proteins, triggering signaling cascades that activate cell-type gene regulatory programs. The cell-cell interactome responds and regulates the microenvironment which is altered in physiological processes such as brain development and aging, or during the onset and progression of different neuropsychiatric disorders. Although great progress has been made in dissecting cellular heterogeneity through single-cell transcriptome and epigenome profiling, a spatial atlas deciphering the gene regulatory programs that mediate cell-cell interactions among neuronal and non-neuronal cell populations in the human nervous system is lacking. New technologies have been developed to generate transcriptome-scale gene expression profiles with high spatial resolution in the original tissue context, thus greatly facilitating the structural characterization of the tissue microenvironment as well as mechanistic investigation of cell-cell interactions. Spatial transcriptomics technologies are increasingly used by the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative and viewed as an important component of the cell atlas building effort. Integrative analyses of spatial transcriptomics and multi-omic data have great potential in constructing a complete spatially resolved brain atlas. However, it remains challenging to systematically analyze, compare, and integrate data generated by different groups, in part due to the significant variation in technology platforms and data analysis pipelines. In previous work, our lab has developed Giotto as a powerful toolbox for comprehensive spatial transcriptomics analysis. In this project, we propose to use Giotto as the basis to create a cloud-based software platform and further develop new pipelines to facilitate harmonizing and integrating BRAIN Initiative datasets. The specific aims are: 1. To develop a cloud-based software platform for harmonizing spatial transcriptomics data analysis and visualization; 2. To elucidate the gene regulatory networks mediating cell- cell interactions in the brain through integrated spatial multi-omic analysis; and 3. To create a benchmark system for objective evaluation of spatial transcriptomics technologies and data analysis pipelines. Taken together, our proposed research will generate powerful computational tools that will not only help BRAIN Initiative investigators to construct a spatially resolved brain atlas but also enable the broad community to efficiently utilize the rich resources generated by the BRAIN Initiative in their own research.