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