Researchers Apply Systems Biology and Glycomics to Study Human Inflammatory Diseases

October 29, 2008

BUFFALO, N.Y. -- An innovative systems biology approach to understanding the carbohydrate structures in cells is leading to new ways to understand how inflammatory illnesses and cardiovascular disease develop in humans. The work was described in two recent publications by University at Buffalo chemical engineers.

Supported by research grants from the National Institutes of Health, the ultimate goal of the project is to define novel strategies to perturb the glycome -- the complete set of an organism's carbohydrate structures in cells -- in ways that lead to the identification of new targets and molecular therapies to combat a broad range of inflammatory diseases.

The binding of white blood cells to blood vessels is a key step in the progression of inflammatory diseases, explained Sriram Neelamegham, Ph.D., UB professor of chemical and biological engineering in the School of Engineering and Applied Sciences, and co-author of both papers. He also is an investigator with UB's New York State Center of Excellence in Bioinformatics and Life Sciences.

"Our goal is to find ways to alter carbohydrate structures or glycans on the surfaces of white blood cells," he said.

But in order to do that, researchers need a far more detailed picture of these structures and the highly complex interactions between glycans, enzymes, genes and proteins, all of which can influence the development of inflammatory disease.

To do this research, Neelamegham's lab uses systems biology, a mathematical and experimental approach that focuses on whole systems of complex biological functions and interactions instead of studying individual units, such as a single gene or protein, in isolation.

"Systems biology is well-suited to this research because it helps us develop the mathematical concepts to enable us to influence and enhance our understanding of how the glycome functions," said Neelamegham. "This then produces clues on how we might manipulate the adhesivity of white blood cells to the blood vessel wall."

Glycans are carbohydrate molecules that mediate the microscopic interactions between white blood cells and blood vessel walls. These interactions play a major role in painful and debilitating inflammatory medical conditions such as asthma, psoriasis, Crohn's disease, reperfusion injury and other cardiovascular ailments.

In a recent paper in The FASEB Journal, the UB researchers describe one of the first studies to take a systems approach to the study of cellular glycosylation, the modification process that is responsible for the attachment of sugar structures to protein and lipid scaffolds. Such biochemical modifications are critical to diverse biological processes, including cell/organ development, immunity and cell adhesion. Abnormal glycosylation also is implicated in diverse diseases, including certain cardiovascular diseases and a cluster of congenital diseases termed Congenital Disorders of Glycosylation.

The paper demonstrates experimental techniques that measure enzyme reaction rates involved in glycosylation, and then draw critical correlations with gene expression, enzyme kinetics and the structures of glycans.

"These techniques enable us to move from genes to proteins and finally to the structures of glycans on cells and individual proteins," said Neelamegham.

The UB paper in Bioinformatics describes a computer model that uses the data produced by those experiments to establish a basis for predicting the structures of glycans on cell surfaces.

"The data produced experimentally allows us to determine key steps in the glycome reaction network that controls the final glycan structure that appears on cells," Neelamegham explained. "This approach then provides an in silico tool that can be applied to perturb the system of interest, such as the glycosylation network."

Those studies, in turn, he continued, can then generate new hypotheses that can be tested experimentally.

"Such an interative approach, using computational and experimental tools, can provide clues as to what reactions must be perturbed in order to alter the carbohydrate structure on cell surfaces in a defined manner," he explained.

The UB researchers noted that their computational and experimental approaches to the problem provide them with a unique insight.

"It's an extremely valuable way to apply engineering principles to biology, it's critical to merge both approaches," said Neelamegham.

In addition to providing new insights for the ultimate development of new drugs and therapeutic strategies, the UB research also is relevant to sectors of the biotech industry, which aim to apply glycan engineering principles during product development.

Coauthors on The FASEB Journal paper, are Dhananjay D. Marathe, research assistant in the UB Department of Chemical Engineering, as well as E.V. Chandrasekaran, scientist, Joseph T.Y. Lau, Ph.D., faculty member, and Khushi L. Matta, Ph.D., faculty member, at Roswell Park Cancer Institute.

Gang Liu, a UB graduate student in the UB Department of Chemical and Biological Engineering, and Marathe and Matta are co-authors on the Bioinformatics paper.

University at Buffalo

Glycome Informatics: Methods and Applications (Chapman & Hall/CRC Mathematical & Computational Biology)
by Kiyoko F. Aoki-Kinoshita (Author)

A Focused, State-of-the-Art Overview of This Evolving Field
Presents Various Techniques for Glycoinformatics The development and use of informatics tools and databases for glycobiology and glycomics research have increased considerably in recent years. In addition to accumulating well-structured glyco-related data, researchers have now developed semi-automated methods for the annotation of mass spectral data and algorithms for capturing patterns in glycan structure data. These techniques have enabled researchers to gain a better understanding of how these complex structures affect protein function and other biological processes, including cancer. One of the few up-to-date books available in this important area, Glycome Informatics: Methods and Applications covers all known...

Glycomics: Methods and Protocols (Methods in Molecular Biology)
by Nicolle H. Packer (Editor), Niclas G. Karlsson (Editor)

Due to the significant contributions of carbohydrates to the functional diversity of the cell, the challenging study of the glycome has expanded beyond the research of carbohydrate experts and into the wider scope of the life sciences. To aid all scientists now delving into this vital subject area, Glycomics: Methods and Protocols collects a compendium of detailed laboratory protocols reflecting the increasing availability of sample preparation, chromatographic, electrophoretic, mass spectrometric, and bioinformatic tools specifically designed for the analysis of glycosylation. Leading researchers in the field address subjects such as glycoprotein and proteoglycan analysis, glycosylation structure determination, as well as various approaches to investigate the interaction between glycans...

Functional remodeling of the cardiac glycome throughout the developing myocardium.
by Marty L Montpetit (Author)

Cell surfaces are replete with complex, biologically important glycans responsible for multiple cellular functions including cell adhesion and cellular communication. Proper protein glycosylation is essential for normal development and often pathologies are marked by altered glycosylation. Here, data showed that the auxillary subunit, beta1, modified voltage-gated Na + channel (Nav) gating in an isoform-specific, sialic acid dependent, and saturating manner. The regulated activity of the hundreds of glycogenes (glycosylation-associated genes) is responsible for protein glycosylation; this could result in a glycome of thousands of glycan structures. Microarray analyses indicated that glycogene expression was highly regulated throughout the heart during development. Specifically, >59% of...

Nanobiotechnology tool for cell surface omics analysis: Superparamagnetic Nanoparticle based high resolution cell surface Proteome, Lipidome & Glycome analysis
by Deepak Balaji Thimiri Govindaraj (Author)

•We present a novel strategy based on cationic phosopholipids-coated superparamagnetic nanoparticles (SPMNPs) to isolate plasmamembranes with very high purity and at a preparative scale;•The SPMNP-based isolation method is compatible with subsequent analysis of the biomolecular composition of plasmamembranes, including proteomcis, lipidodomics and N-glycomics analysis. •A comparative ‘omics’ analysis of plasmamembranes from wild-type, presenilin deficient and human presenilin1 rescued fibroblasts revealed convergent changes in proteins and lipids suggesting an underlying endosomal transport deficit. •Our methodology allows for the systematic set-up of comprehensive plasmamembrane inventories: alterations in the composition of the cell surface may potentially identify novel...

Glycome Informatics: Methods and Applications (Chapman & Hall/CRC Mathematical & Computational Biolo [Hardcover]
by Kiyoko F. Aoki-Kinoshita (Author)

Handbook of Glycomics
by Richard D. Cummings (Editor), J. Michael Pierce (Editor)

'This handbook provides the first comprehensive overview of the emerging field of glycomics, defined as the study of all complex carbohydrates in an organism or cell ("the glycome"). Beginning with analytic approaches and bioinformatics, this work provides a detailed discussion of relevant databases, data inegration, and analysis. It then moves on to a discussion of specifc model organism and pathogen glycomes followed by therapeutic approaches to human disorders of glycosylation. Structure and function of glycomes are included along with state-of-the-art technologies and systems approaches to analysis of glycans.

* Synthesizes contributions from experts in biology, chemistry, bioinformatics, biotechnology, and medicine

* Highlights...

Essentials of Glycobiology, Second Edition
by Ajit Varki (Editor)

The sugar chains of cells - known collectively as glycans - play a variety of impressive, critical, and often surprising roles in biological systems. Glycobiology is the study of the roles of glycans in the growth and development, function, and survival of an organism. Glyco-related processes, described in vivid detail in the text, have become increasingly significant in many areas of basic research as well as biomedicine and biotechnology. This new edition of Essentials of Glycobiology covers the general principles and describes the structure and biosynthesis, diversity, and function of glycans and their relevance to both normal physiologic processes and human disease. Several new chapters present significant advances that have occurred since the publication of the first edition. Three...

Carbohydrate Bioengineering: Interdisciplinary Apporaches (Special Publication)
by T.T. Teeri (Editor), B. Svensson (Editor), H.J. Gilbert (Editor), T. Feizi (Editor)

Carbohydrate bioengineering is a rapidly expanding field with many applications in medicine and industry. Presenting state-of-the-art research, "Carbohydrate Bioengineering: Interdisciplinary Approaches" brings together international experts on many different aspects of this burgeoning topic. Coverage includes: the engineering of gkycosidases for constructive purposes; structure-function studies and protein engineering of carbohydrate-active enzymes; chemo-enzymatic carbohydrate synthesis; and trends emerging from comprehensive work on genomes and glycomes. This timely publication will be welcomed by all those needing access to the latest research in the field, including practitioners in the medicinal, chemical, food and pharmaceutical areas.

Glycomics, Volume 478 (Methods in Enzymology)
by Minoru Fukuda (Series Editor)

In this 3 volume collection focusing on glycomics, readers will appreciate how such discoveries were made and how such methods can be applied for readers' own research effortsEach chapter has been designed so that enough scientific background will be given in each chapter for further development of methods by readers themselves. Useful for all levels of scientists starting from the last years of colleges, graduate students, postdoctoral fellows to professors and to all levels of scientists in research institutes including industry.