Protein post-translational modifications (PTMs) have emerged in the post-genomic era as critical features in regulating and diversifying protein biological activity. However, identifying specific proteoforms with PTMs is currently limited by the lack of effective and accessible analytical methods. The overall purpose of my research program is to establish a high-throughput quantitative top-down proteomics platform that combines top-down mass spectrometry (MS) and novel technologies. Specifically, our top-down MS studies are based on applying high-resolution reversed-phase liquid chromatography (RPLC) based separations (high pH and/or low pH) and isobaric labeling-based analysis of intact proteins for quantitation of complex protein mixtures. In particular, we are applying top-down proteomics to analyze serum autoantibodies in patients with systemic lupus erythematosus (SLE), which holds the potential to provide new insights regarding the autoantibody affinity maturation process and may lead to novel biomarkers for the diagnosis and treatment of SLE. We are also developing novel analytical tools for quantitatively extracting ultra-low volume samples (e.g., single cell) for proteomics such as the “spray-capillary”. Overall, we envision these techniques as novel analytical tools to apply to the rapidly expanding field of real-life proteomics.