National Center for Translational and Developmental Proteomics

Despite the central role for proteins as primary mediators of cell phenotype and function, proteomics has lagged genomics and transcriptomics as a tool for fundamental and translational biomedical research. There is a significant deficit in our knowledge of functional post-translationally modified forms of proteins, i.e. proteoforms, and the role of proteoform dynamics in health and disease. Technologies to readout proteoform biology are neither hardened nor easily adopted by the community at large. Despite an increasing number of first-wave commercial solutions over the last five years, the academic proteomics community has yet to integrate top down mass spectrometry approaches to proteomics into mainstream practice. We are proposing a new National Center for Translational and Developmental Proteomics (NCTDP) that will leverage the top down mass spectrometry methods developed over the past 9 years of NIGMS funding to optimize and disseminate cutting edge methods for proteoform discovery and measurement to the scientific community. The goals of the NCTDP are (1) achieve impactful outcomes for Driving Biomedical Projects; (2) reduce to practice selected technologies; and (3) and broaden access to new top down proteomics methods via robust dissemination across academic and industry research communities. These goals will be achieved using a four-pronged approach. First, we will optimize and beta test impactful workflows for proteoform measurement through three Technology Optimization Projects in preparation for dissemination and commercialization. Second, we will advance the mapping and robust measurements of proteoforms in basic and translational biomedical research through 10 Driving Biomedical Research Projects (DBPs). Third, the Center’s Community Engagement program will engage academic-, government-, and industry-based proteomics communities through on-site training, beta testing, and professional webinars. Implementation of NCTDP technologies as service lines in the well-established Northwestern Proteomics Core, plus hands on training for core directors from across the country, will enable broad access to Center technologies for external investigators and their students. And finally, we will provide robust leadership and supporting infrastructure that will facilitate integration of the technology optimization goals, effective execution of driving biomedical projects, and vigorous community engagement. The proposed NCTDP will harden the current generation of technologies for discovery and targeted measurement of proteoforms to bridge top down mass spectrometry with other -omics and single-molecule protein sequencing. The Center’s outreach and dissemination initiatives will address protein knowledge gaps and will significantly improve the capabilities of the research community to (a) better detect and assign function to proteoforms, their isoforms and PTMs, (b) create exportable assays to probe the early onset of cellular and disease phenotypes, and (c) determine new targets for more precise development of drugs and chemical probes. This expanded tool kit will usher in a new era of proteoform systems biology and biomedical research.