The biomedical relevance of disease-related alterations in protein glycosylation has been recognized for some time. However, significant challenges remain in translating these observations into robust disease biomarkers, and in establishing a detailed molecular understanding of how altered protein glycosylation affects a diverse variety of biomolecular interactions and protein structure / function interplays. Because protein glycosylation is the end result of complex non-template-driven biosynthetic processes, a protein glycoform profile is exquisitely sensitive to metabolic irregularities, including those that accompany disease. For these reasons, the detailed molecular characterization of protein glycosylation is of great biomedical interest in the context of disease biomarker discovery, and for the purpose of relating disease-induced alterations of protein glycosylation to protein function. Essential to such endeavors are powerful analytical techniques that can determine the compositions and structures of protein-linked glycans and their sites of protein attachment in complex and heterogeneous mixtures. This application to the MIRA program requests support of a research program dedicated to the advancement of biomedical glycoproteomics through the development, application, and dissemination of mass spectrometry, tandem mass spectrometry, and ion mobility spectrometry based tools for interrogating the glycoproteome and determining site-specific protein glycoforms. The goals of this program are consonant with current NIH priorities, including the recent calls for increased investment in early stage development of new technologies for biomedical research and ongoing initiatives to catalyze advancements in glycoscience. The new technologies that will result from this work will be generalizable and thus applicable to the elucidation of site-specific protein glycoform patterns in an eclectic array of biomedically-relevant contexts.
Most proteins are naturally decorated with sugars, and it is well-known that many diseases are caused by or result in changes to the number or types of sugars that are attached to proteins. This is of great significance to human health because these changes can alter protein structure, function, and activity, and may be useful for detecting disease. This research program is dedicated to the development of novel and innovative analytical tools that can be used to characterize the biomedically relevant profiles of the sugars that modify proteins.
| Aboufazeli, Forouzan; Dodds, Eric D (2018) Precursor ion survival energies of protonated N-glycopeptides and their weak dependencies on high mannose N-glycan composition in collision-induced dissociation. Analyst 143:4459-4468 |
