The Huang Laboratory at Scripps Research employs integrated chemical approaches to bridge the glycome and proteome in order to control cancer biology and stem cell fates. We employ techniques in synthetic chemistry, analytical mass spectrometry, and protein engineering to illuminate the fundamental mechanisms of glycan-protein biology. These investigations include probing the role of proteoglycan structure in stem cell fates, the development of methodologies to systematically map the interactions between glycans and proteins, as well as the exploration of chemical space to target glycans in cancer. Knowledge resulting from these research programs will present new avenues for modulating cancer biology and stem cell differentiation, as well as pave the discovery of new agents to access them for biomedicine.
More than half of the global cellular proteome is estimated to be post-translationally modified with glycans. Defects in glycosylation can have profound effects towards human physiology and can direct pathological consequences. We are interested in identifying areas of the cell that possess the capability to decorate proteins with glycans and understanding how these modifications can impact fundamental cellular processes.
Proteoglycans are macromolecular glycoconjugates that play critical roles in templating stem cell differentiation. Proteoglycans are composed of a core protein modified with long-chain glycosaminoglycan chains, and this project seeks to understand the effects imparted by specific glycosaminoglycan chains within the context of the core protein. Our ultimate aim is to uncover how proteoglycan architecture and organization governs cellular fates and to use this information towards applications in regenerative medicine.
This work is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Glycans play important roles in fundamental cellular processes and disease. For example, nascent proteins are N-glycosylated and processed in the ER in order to check for proper protein folding. Defects in this processing machinery can cause deleterious consequences. In cancer, aberrant or atypical glycosylation, caused by misregulated expression of biosynthesis enzymes, can endow cells with the capacity to migrate or metastasize. This project seeks the development of chemical tools to correct these faulty mechanisms.
Today, glycoscience sits at a crossroads. It can continue to be a specialty practiced by a smattering of investigators studying specific problems. If the field stays on that path, it will surely continue to generate important insights but not at a rate that will allow it to live up to its enormous potential … and to address major problems in human health… or glycoscience can take advantage of advances in genomics, proteomics, chemical synthesis, microbiology, microfluidics, biochemistry, and nanotechnology, to not only enable a more aggressive and comprehensive effort involving a large cadre of researchers but also to provide a blueprint for realizing the transformative leaps in technology and methods that make such an effort feasible and likely to generate enormous benefits to society.
- Transforming Glycoscience: A Roadmap for the Future. National Research Council. 2012. Transforming Glycoscience: A Roadmap for the Future. Washington, DC: The National Academies Press.