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Departments: Glycomics & Glycoprotemics

Ryan Weiss

jennbryant on July 20, 2021

Short Biography:
Dr. Ryan Weiss received his B.S. in chemistry in 2008 at Point Loma Nazarene University in San Diego, CA. He then received his Ph.D. in chemistry in 2015 at the University of California, San Diego under the supervision of Prof. Yitzhak Tor. He then moved to the Department of Cellular and Molecular Medicine at the University of California, San Diego, where he worked as a postdoctoral fellow in the laboratory of Prof. Jeffrey Esko. Dr. Weiss began his independent career as an assistant professor in the Department of Biochemistry and Molecular Biology at the University of Georgia in January 2021. His current research interests include drug discovery and using genomic tools to understand the regulation of glycosylation in human diseases.

Research Interests:
Complex carbohydrates play important roles in many cellular processes and their dysregulation has been implicated in many disease states, including cancer, pathogen infection, and rare genetic disorders. The mammalian glycome contains extensive structural and functional heterogeneity that can vary temporally and spatially during development and in different tissues. Currently, little is known about the regulation of the non-template driven assembly of these ubiquitous post-translational modifications. My current research interests are focused on studying the structure, function, and genomic regulation of complex carbohydrates in human biology and disease. In particular, my laboratory is focused on identifying the transcriptional and epigenetic programs responsible for temporal and spatial control of glycosylation using genome-wide, molecular, and chemical approaches. In addition, we are dedicated to developing pharmacological and cell-based tools to aid in the discovery of novel targets and therapies for modulating glycan and glycoprotein expression in human diseases.

  • Functional Genomics of Glycosaminoglycan Biosynthesis

In the Weiss lab, we utilize pooled genome-wide CRISPR screening approaches, genetic engineering, and bioinformatic tools to identify the molecular mechanisms responsible for the regulation of glycosaminoglycan biosynthesis in human cells.

 

  • Drug Discovery for Rare Genetic Disorders

Many human diseases are caused by rare mutations in genes involved in the biosynthesis and/or catabolism of glycans. In the Weiss lab, genetic engineering, high-throughput drug screening, and cell-based disease models are utilized to uncover novel drug targets and therapeutic agents to treat these rare genetic disorders.

 

  • Epigenetic and Transcriptional Regulation of Glycan Assembly

Epigenetic changes alter the physical structure and organization of DNA, and transcription factors regulate the expression of their genomic targets. Currently, little is known about the genomic regulation of glycosylation. The Weiss lab aims to use state-of-the-art genomic tools and pharmacological agents to identify and modulate novel regulatory pathways responsible for controlling glycosylation in mammalian cells.

Lance Wells

jennbryant on July 12, 2021

Short Biography:
Dr. Wells received his B.S. in Chemistry, with a minor in Psychology, in 1991 from the Georgia Institute of Technology, and after spending two years working at the Microchemical Facility, his Ph.D. in Biochemistry and Molecular Biology in 1998 from the Emory University School of Medicine. A postdoctoral research fellowship at the Johns Hopkins School of Medicine in Biological Chemistry followed, which was supported by a National Research Service Award from the National Cancer Institute of the NIH. Dr. Wells joined the CCRC in August of 2003. Full publications: 98.

Research Interests:
Using a combination of methodologies, including mass spectrometry, protein biochemistry, cell biology, genetics, proteomics, and molecular biology, we study the role of PTMs (primarily O-glycosylation) in a variety of pathophysiological processes including cancer, diabetes, viral infection, neurological disorders, and congenital muscular dystrophy. Our research is aimed at increasing our understanding of how increased functional diversity leads to finer control of biological processes. The hope is that by understanding the role of PTMs, we will not only more accurately describe fundamental biological processes but will also elucidate novel therapeutic targets in disease states where these processes have become dysregulated.

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Michael Tiemeyer

jennbryant on July 12, 2021

Short Biography:
Dr. Tiemeyer received his B.A. in biology in 1982 and his Ph.D. in neuroscience in 1989 from The Johns Hopkins University. He was a Helen Hay Whitney postdoctoral fellow in developmental neurobiology at the University of California at Berkeley. Prior to joining the CCRC faculty, Dr. Tiemeyer was a faculty member in cell biology at Yale University School of Medicine and Director of Biochemical and Clinical Analytics and New Methods Development at Glyko/Biomarin, Inc. Full publications: 27.

Research Interests:
The surfaces of all eukaryotic cells are richly endowed with a diverse array of complex glycoconjugates. Therefore, carbohydrate moieties linked to protein, lipid, and glycosaminoglycan form the interfaces at which cell-cell interactions occur. Consistent with their subcellular location and structural diversity, specific oligosaccharides function as cell-surface tags that allow cells to appropriately interact with each other and with their local environment. In fact, cell surface carbohydrates are among the most discriminating markers for cellular differentiation and pathogenesis. We utilize genetic, molecular, and chemical techniques in vertebrate (mouse) and insect (Drosophila) model systems to study two aspects of carbohydrate expression. First, we investigate the influence of cell surface carbohydrates on development of the nervous system. We identified and characterized a novel carbohydrate binding protein (Gliolectin) that mediates the fidelity of axon pathfinding early in neural development. Second, we study mechanisms that control tissue- and stage-specific oligosaccharide expression. We discovered that a member of the Toll-like receptor family (Tollo) influences tissue-specific glycosylation through cell-cell communication. Our results have implications for facilitating regeneration of axon pathways in the nervous system, for understanding innate immunity and tissue surveillance, and for controlling the cellular changes that precede tumor metastasis.

Christine Szymanski

jennbryant on July 12, 2021

Short Biography:

Dr. Szymanski has been exploring bacterial glycomics for three decades, working on food pathogens since the early 1990s, with a particular emphasis on Campylobacter jejuni. She combines her expertise in food safety and animal health with novel therapeutic diagnostic platforms developed during her postdoctoral fellowship at the Naval Medical Research Center vaccine program (1996-2000), the key findings while employed at the National Research Council of Canada (2000-2008), and the translational advances during her tenure as an Alberta Innovates Technology Futures Scholar at the University of Alberta (2008-2016). She was the first to demonstrate that bacteria are capable of N-glycosylating proteins and is now exploiting these systems to create glycoconjugate vaccines and oral therapeutics through recombinant expression in Escherichia coli. Dr. Szymanski was also the first to demonstrate that viruses specific for bacteria express proteins that can be used as novel therapeutics in addition to their recognized diagnostic value. These viruses (bacteriophages) are the most abundant biological entity on earth (10+31) and are therefore a limitless resource for exploitation, especially in the area of glycomics.

Research Interests:

The Szymanski laboratory is a microbial glycobiology laboratory using multidisciplinary techniques and relevant model systems to: 1) characterize bacterial glycoconjugate pathways, 2) exploit bacteriophage recognition proteins that bind these structures, and 3) understand the protective benefits of host milk oligosaccharides to develop novel therapeutics and vaccines for the prevention of diarrheal diseases and post-infectious neuropathies such as Guillain-Barré Syndrome. These studies have also expanded our knowledge of carbohydrate metabolism by the gut microbiota and the transfer of antibiotic resistance between bacteria.

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Michael Pierce

jennbryant on July 12, 2021

Short Biography:
Dr. Pierce received his Ph.D. in biology in 1980 from the Johns Hopkins University. Prior to joining the CCRC in April 1991, Dr. Pierce was assistant then associate professor in the Department of Cell Biology and Anatomy at the University of Miami School of Medicine and Staff Investigator of the Papanicolau Comprehensive Cancer Center. In 1988 he was the recipient of a five-year Faculty Research Award from the American Cancer Society. He now serves on the editorial boards of the Journal of Biological Chemistry and Glycobiology. He now serves as Co-Chair of the Alliance for Glycobiologists for Cancer Detection, the Cancer Biology Chair of the Consortium for Functional Glycomics, and 2015 President of the Society for Glycobiology. He is P.I. of the NIGMS National Center for Biomedical Glycomics and Co-P.I. of the NIH Glycoscience Predoctoral Training Program (GTP). His funding comes from NIGMS and NCI.

Research Interests:
Glycan structures change during oncogenesis; these changes are often hallmarks of cancer progression. Our lab investigates:
What are the precise glycan structural changes that occur?
How these changes are regulated at the molecular level?
What are the functional consequences of these changes?
Can these changes be exploited to develop potential diagnostics or therapeutics?
We isolated a cDNA encoding a glycosyltransferase whose activity and product is increased in many cancers, particularly epithelial-derived and showed that its transcript was upregulated via the ras-raf-ets oncogenic signaling pathway.
Our main focus now is on a unique N-glycan whose expression is only on a few proteins in the human genome (protein-site-specific) and appears to be an excellent marker for pancreatic carcinoma.
Discovery of a novel family of innate immune lectins

The X-lectin family is found in deuterostomes from the sea cucumber to man
Over 240 sequences from lectins in this family are now in the database
We isolated the Xenopus laevis cortical granule lectin and with Kelley Moremen showed that it had two human homologs
These human homologs, the intelectins, are constitutively expressed in various endothelial cells, Paneth cells, and are induced in respiratory and intestinal epithelia by IL-13, an innate immune cytokine produced by immune cells
Recent results show intelectin-1 binds and kills specific pathogenic bacteria
We are defining the specificities of the binding sites on various intelectins and working to discover their structures and functions
Here is a recent seminar that I presented as part of the Goldstein Lectureship, University of Michigan Department of Biochemistry and Molecular Biology.

Ron Orlando

jennbryant on July 12, 2021

Short Biography:
Dr. Orlando received his B.S. in natural science in 1983 from St. Mary’s College of Maryland and his Ph.D. in analytical chemistry in 1988 from the University of Delaware. He joined the CCRC in January 1993. He heads the CCRC’s mass spectrometry facility and was named a “Leader of Tomorrow” in 1995 by the journal Spectroscopy. In 1996 he was invited by the journal Analytical Chemistry to review the MS calculator Softshell. He has two U.S. patent applications pending. Dr. Orlando is a frequently invited seminar speaker at international colloquia and at research institutes, academic departments, and industrial organizations around the world. He was invited by the ACS Divisions of Analytical and Carbohydrate Chemistry to organize a session entitled, “Advances in Mass Spectrometry of Carbohydrates” at the 211th National Meeting of the American Chemical Society in March 1996 and chaired a session entitled, “Mass Spectrometry in the 21st Century” at the SUNBOR 50th Anniversary Symposium in Osaka, Japan, in June 1996. Full publications: 50.

Research Interests:
Dr. Orlando conducts research on using mass spectrometry (MS) to answer biological questions. He also is concerned with developing new methodologies to increase the amount of information obtained from MS experiments and to reduce the quantity of material needed for analysis. The procedures Dr. Orlando and his group have developed can currently elucidate the complete primary structures of the carbohydrate side chains of glycoproteins (including the stereochemistry, linkage, and anomeric configuration of each monosaccharide) from only low picomole quantities of sample.
The carbohydrate side chains of enzymatically glycosylated proteins play important, often essential, roles in the functions of glycoproteins. Carbohydrates linked through asparagine residues (N-linked) of glycoproteins participate in such health-related processes as hormone action, cancer, viral infection, and cell development and differentiation. The biological functions of carbohydrate chains attached through serine or threonine residues (O-linked) of glycoproteins are less well-defined, although these carbohydrate chains appear to be required for the biosynthesis, secretion, and compartmentalization of some glycoproteins. Alternatively, the non-enzymatic glycosylation (glycation) of proteins is believed to disrupt the normal structure and function of proteins and has been implicated in a range of health problems, particularly those associated with diabetes such as the development of cataracts.

The structural characterization of complex biologically active glycoproteins, essential to understanding their biological functions, currently holds numerous challenges for the biomedical researcher. Biomedically relevant glycoproteins typically can only be isolated in picomole quantities, while many of the techniques available for structurally analyzing the carbohydrate chains require at least nanomole quantities of material. Furthermore, no generally applicable strategy has been developed to determine O-linked glycosylation sites. The most widely used techniques for studying the carbohydrate portions of glycoproteins incorporate chemical or enzymatic release of the carbohydrate side chains from the peptide backbone prior to their structural analysis. However, the separation of the carbohydrate side chains from the peptide means that the point of attachment for each carbohydrate chain and the carbohydrate heterogeneity at each glycosylation site cannot be determined.

Dr. Orlando and his group are involved in several research projects that will continue their development of new MS strategies to structurally characterize glycoproteins. This work focuses on analyzing glycopeptides prior to removal of their carbohydrate side chains and reducing the sample quantities required for these MS procedures. Currently, they can characterize the complete primary structure of a glycoprotein from only 1-10 picomole of sample, approximately 5,000 times less material than is needed for present conventional methods. This work is also expected to produce general schemes for analyses that are particularly challenging for existing methodology, such as determining O-linked glycosylation and/or glycation sites. As new techniques are developed and refined, they are used to structurally characterize biologically significant glycated and glycosylated proteins.

For example, the discovery of elevated levels of glycated albumins and hemoglobins in diabetic patients has focused attention on the roles played by glycation in a range of health-related problems. Glycation is prevalent in diabetics in particular because of the frequent occurrence of high blood sugar levels in these patients. This modification of protein chains results from the irreversible addition of a saccharide to the free amino groups of lysines or the N-terminus of a protein. However, the lack of sensitive analytical procedures to structurally characterize glycated proteins has limited most research in this area to those glycated proteins that are easily obtained in large quantities, rather than to being able to study the effects of glycation in critical biomedical processes. Glycation of difficult-to-obtain proteins, therefore, may be responsible for a number of health-related problems in diabetics, including the development of cataracts. Glycation is believed to play a role in cataract development because it purportedly disrupts the structure of the eye lens proteins (crystallins). The tight, stable packing of the crystallins provides the optical characteristics necessary for vision. When this packing is disrupted by glycation, the refractive index of the lens is altered, causing light scattering and eventual lens opacity (cataracts).

Dr. Orlando’s group is investigating the structural characterization of crystallins obtained from human eye lenses of healthy and diabetic patients. A major goal of this investigation is to determine the extent of crystallin glycation and the sites of sugar attachment in the crystallins of diabetic patients as compared to healthy individuals to learn more about the role of glycation in cataract development. The techniques developed during the study of glycated crystallins are expected to open up new areas of investigation concerning the role of glycation in other health-related problems associated with diabetes, such as kidney dysfunction, osteoporosis, and osteopenia. Dr. Orlando’s work is supported by the National Institutes of Health, the National Science Foundation, and industrial sources.

Parastoo Azadi, Ph.D.

jennbryant on June 28, 2021

Short Biography:
Dr. Azadi received her B.Sc. in Chemistry in 1987 from University of North London, UK and her Ph.D. degree in biochemistry in 1991 from Imperial College of Science and Technology, University of London, studying structural characterization of carbohydrates and glycoproteins by mass spectrometry under the supervision of Profs. A. Dell and H.R. Morris.
In 1990 through to 1994 she was the senior scientist and the study director at M-Scan limited, an Analytical Mass Spectrometry Consultancy in UK where she was responsible for complete structural characterization of native and recombinant proteins and glycoproteins using mass spectrometry as a service to the pharmaceutical industry.

In 1994 she joined the Complex Carbohydrate Research Center as a postdoctoral fellow and studied the effect of the enzymes endohyrolase and endolyase on rhamnogalacturonan I, and characterization of the fragments produced by these enzymes by ESI-MS and ESIMS/MS. In 1996 she became the Associate Technical Director of plant and microbial Analytical Services at the Complex Carbohydrate Research Center where she was responsible for plant and microbial service program where polysaccharides and lipopolysaccharides were analyzed for other institutes.

Since 2001, Dr. Azadi has been the Technical Director of Analytical Service and Training at the Complex Carbohydrate Research Center. As the Technical Director, the she oversees and manages all analytical services and training conducted at the CCRC, which are supported by three federal resource centers of excellence that CCRC has been awarded: The Department of Energy-funded Center for Plant and Microbial Complex Carbohydrates, the National Institutes of Health Resources Center for Integrated Glycotechnology, and the National Institutes of Health for Biomedical Glycomics. The analytical service program offers two main areas of service: standard analyses and contract analyses. The samples submitted for these types of analyses come from academic, government, non-profit organizations and private companies, throughout the United States and internationally.

Dr. Azadi works closely with the research scientists in industry on developing carbohydrate based drugs and the need for out-sourcing prior to phase I and phase II clinical trials.

Her laboratory also conducts research in areas of structural characterization of plant, bacterial and animal polysaccharides, glycoproteins and glycolipids using MS and NMR techniques.

Research Interests:
Structural analysis of oligosaccharides, glycoproteins, polysaccharides and glycolipids by mass spectrometry.

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