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Northwestern's Kelleher Awarded $7.5M Grant to Advance Top-Down Proteomics


NEW YORK (GenomeWeb) – Northwestern University researcher Neil Kelleher has received a five-year, $7.5 million grant from the National Institute of General Medical Sciences to fund the development, application, and dissemination of top-down proteomics as a tool for translational research.

Called the National Resource for Translational and Developmental Proteomics (NRTDP), the effort includes the participation of academic and industry collaborators across the country, and aims to improve the whole-protein quantitation technology developed in Kelleher's lab while demonstrating its potential in clinical settings, he told GenomeWeb.

The NRTDP also includes a formal program through which investigators from other institutions can visit Northwestern to learn top-down proteomics and begin applying it in their own labs, Kelleher added.

Unlike conventional bottom-up proteomics, in which proteins are digested into peptides and then identified by liquid chromatography and tandem mass spectrometry, top-down proteomics involves the identification of proteins directly from fragmentation of an intact protein, offering richer data around a protein and its molecular composition.

Kelleher has been a leading figure in top-down proteomics, reporting in 2011 on its use to identify 1,000 unique proteins and 3,000 proteoforms. In 2013, his lab conducted the largest top-down proteomics study of a human cell line to date, identifying 1,220 proteins and more than 5,000 proteoforms in H1299 cells.

And earlier this year, he and collaborators published a workflow for label-free quantitation in top-down proteomics.

To further drive the growth of top-down proteomics and with the support of the NIGMS grant, Kelleher this month kicked off the NRTDP initiative to further refine the technology and improve its accessibility to other groups.

The NRTDP comprises three main activities. Under the first, the core top-down proteomics pipeline developed in Kelleher's lab will be further refined, bringing together "better chromatography, better mass spectrometry, [and] better performance at high mass," he said. "The vision is to be able to get more and more proteome coverage from less and less sample."

The second involves applying the technology to various clinical applications including the identification of biomarkers in B-cell cancers such as chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia.

In partnership with the Mayo Clinic, Kelleher and his team aim to identify protein biomarkers that can be used for the early detection of these cancers and for the stratification of patients based on their antibody-expression profiles, he explained.

The NRTDP will also work with National Institutes of Health-funded collaborators in the area of kidney transplantation, looking for proteins that may help identify patients who will reject their new organs, and in oncofertility, trying to pinpoint proteins involved in maintaining the viability of cryopreserved ovarian follicles from female cancer patients.

Lastly, the NRTDP will facilitate the training of scientists, Kelleher said, noting that researchers have been visiting his lab over the years to learn top-down proteomics, but only informally.

"Now, we actually have a structured [visitation] program," which will be overseen by a soon-to-be-named outreach director and will include follow-ups to "make sure that the translation of what they learned is functional in their home shop," he said.

At the end of the grant's five-year term, Kelleher said that he hopes to have proof that proteoforms are valuable, and an estimate of their value.

"If you do that, you show people what the power of direct observation versus peptide inference can be," he said. Anecdotal evidence has established a correlation between top-down proteomic data and complex phenotypes such as disease states, "but no one knows how much that is true and … how much that is worth. Translational proteomics could use a really good shot in the arm of additional value."