Abstract While rapid advances in single-cell RNA-sequencing are yielding comprehensive taxonomies of cell states in the human body, understanding the complex molecular and environmental factors that regulate cell behavior remains a central challenge. New methods for simultaneous measurement of multiple molecular modalities, spatial context, and lineage relationships are needed to address this goal, but are currently outside the scope of present technologies which largely focus on a single data type. We propose to create a Center for Integrated Cellular Analysis, with a mission to develop a comprehensive suite of technologies and analytical methods to measure and integrate the molecular and environmental determinants of cellular identity. To achieve these goals, we propose the following series of synergistic Aims that will be developed in parallel: 1) Develop massively- parallel assays to simultaneously profile multiple molecular components across millions of cells; 2) Identify the spatial and environmental determinants of cellular state in complex interacting populations; 3) Develop scalable platforms to profile inherited molecular components, and determine the role of cell lineage in establishing molecular and phenotypic differences across cells; and 4) Develop methods to harmonize single- cell profiles across distinct modalities, enabling the inference of cellular identity. Our Center will address critical challenges in data integration, and produce software and protocols that will be applicable to diverse biological systems. We will share these resources broadly with the community, alongside a broader educational focus to encourage New York City students from under-represented backgrounds to pursue academic training in Genomics and Systems Biology.

Project Narrative Understanding how the molecular components, inherited lineage, and spatial milieu of single cells dictate function in health and disease remains a key outstanding challenge in genomics. The overarching goal of our Center for Integrated Cellular Analysis is to develop methods to simultaneously assess these multimodal cellular properties, develop tools to harmonize them to allow inferential assessment of cell identity based on partial phenotyping, and share these developments with the broad scientific community while encouraging community engagement through education and outreach. Success in our strategy will facilitate deep, multi-omic phenotyping of single cells for basic research and clinical applications.