ABSTRACT Droplet-based single cell transcriptome sequencing (scRNA-seq) technology is able to measure the gene expression from tens of thousands of single cells simultaneously. More recently, coupled with cutting-edge Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and Cell Hashing technology, the droplet-based system has allowed for immunophenotyping of single cells based on cell surface expression of specific proteins together with simultaneous transcriptome profiling in the same cell. These cutting-edge technologies have transformed biomedical research. The proposed two projects in this P01 renewal will apply these single-cell genomics tools to further characterize the molecular signature of severe asthma patients and advance our knowledge of underlying pathobiological characteristics. Bioinformatics and sequencing Core C will provide full support to both projects with the knowledge from the best single cell experiment and bioinformatics practice in the field. With the similar responsibility of Core C in the previous cycle, our core will continue providing high-quality services of cutting-edge single cell experiments and advanced bioinformatics analysis. In addition to classic analysis, Core C will develop new computational tools to analyze single-cell multi-omics data and integrate multi-modal data with clinical phenotypes from both projects. Specifically, the aims of our team are to: (1) perform bulk RNA-seq, TCR-seq, scRNA-seq and CITE-seq experiments, (2) perform data processing and advanced bioinformatic analysis of multi-omics data, and (3) develop novel and tailored computational methods for integrative analysis of multi-omics single cell data. To achieve our goals, we have assembled a multidisciplinary team with outstanding expertise in asthma research, single-cell technology, bioinformatics, and computational immunology. Our pioneering work should generate precious genomics data, enhance our understanding of asthma pathogenesis, and provide new biological insights to prevent, diagnose, and treat severe asthma.