Coupling Quantitative Biological Mass Spectrometry with Genetic Manipulation to Understand How Proteins Contribute to Disease and the Efficacy of Therapies
Using biological mass spectrometry and other proteomics-based methods, the James Lab investigates how proteins become dysregulated in inflammatory disease and lymphoma. These techniques can be used to evaluate changes in protein abundance and protein modifications (including phosphorylation, ubiquitylation, and acetylation), alterations in cell membrane and nuclear protein expression, changes in protein-protein interaction partners, etc. in disease states and upon pharmacological treatment or genetic manipulation. This quantitative data helps us understand which signaling pathways contribute to disease and which prevent effective responses to specific therapies.
Dr. Richard James
Using this established framework for integrating genetic and quantitative proteomics data, James’ research is increasing our understanding of how pathogenic gene variants found to be associated with asthma, diabetes, lupus and other inflammatory disease impact the proteome of immune cells. By modeling how specific genetic variants alter global protein function in pathogenic cells and by determining how the protein-protein interaction networks of these proteins are altered in the variant setting, James hopes to develop targeted mass spectrometry-based assays that can be used clinically to predict which therapies may be effective in patients that express these variants.
In addition to his work in inflammatory diseases, James is also investigating why some patients with B cell lymphoma develop resistance to targeted therapies, specifically kinase inhibitors. The goals of this work are to:
- Identify signaling programs expressed in resistant cells that enable their survival in the presence of inhibitors
- Discover drugs or therapeutics that will effectively kill these drug-resistant cancer cells
- Identify protein-based biomarkers that will predict whether and when a patient is likely to develop resistance while undergoing treatment
James is interested in establishing industry collaborations in which his expertise in quantitative proteomics and targeted mass spectrometry can be utilized to understand and monitor aberrant cellular signaling in inflammatory diseases and lymphoma. The James Lab is also interested in leveraging their proprietary data sets to develop antibody and/or small molecule targeting reagents in an effort to target protein-based pathways that promote drug resistance or pathogenesis in inflammatory disease.
- Tampella G, Kerns HM, Niu D, Singh S1, Khim S, Bosch KA, Garrett ME, Moguche A, Evans E, Browning B, Jahan TA, Nacht M, Wolf-Yadlin A, Plebani A, Hamerman JA, Rawlings DJ, James RG. The Tec Kinase-Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages. J Immunol. 2015; 195:246-56. doi: 10.4049
- James RG, Bosch KA, Kulikauskas RM, Yang PT, Robin NC, Toroni RA, Biechele TL, Berndt JD, von Haller PD, Eng JK, Wolf-Yadlin A, Chien AJ, Moon RT. Protein kinase PKN1 represses Wnt/β-catenin signaling in human melanoma cells. J Biol Chem. 2013; 288:34658-70. doi: 10.1074
- Dai X, James RG, Habib T, Singh S, Jackson S, Khim S, Moon RT, Liggitt D, Wolf-Yadlin A, Buckner JH, Rawlings DJ. A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models. J Clin Invest. 2013;123:2024-36. doi: 10.1172
Stage of Development
- Pre-clinical in vitro
- Pre-clinical in vivo
- Pre-clinical ex-vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, please contact:
Dr. Elizabeth Aylward
Director, Office of Science-Industry Partnerships