cules consist of carbohydrate structures covalently 
linked to membrane-associated proteins and lipids. 
Many of these structures undergo striking changes 
during development and differentiation and in asso- 
ciation with neoplastic transformation. Numerous 
experimental observations suggest that cell surface 
oligosaccharides function as information-bearing 
molecules that mediate communication between 
cells and their environment during development 
and differentiation. The structure of cell surface oli- 
gosaccharides is determined primarily by glycosyl- 
transferase enzymes. Molecular mechanisms respon- 
sible for the regulation of expression of these 
enzymes, and thus the expression of cell surface gly- 
cocon jugate structure, remain poorly defined. More- 
over, in most instances the precise function (s) of 
the oligosaccharide structures determined by these 
enzymes is also obscure. The major goals of Dr. 
Lowe's research efforts are to understand 1) the 
mechanisms that regulate expression of cell surface 
oligosaccharide antigens and 2) the functions of 
these molecules, through approaches involving the 
use of cloned glycosyl transferase gene segments. 
Dr. Lowe's laboratory is investigating representa- 
tive human and murine glycosyltransferase genes as 
models to understand glycosyltransferase structure 
and regulation and the function (s) of their oligosac- 
charide products. These enzymes include fucosyl- 
transferases, whose expression is determined by the 
human H and Lewis blood group genes, and struc- 
turally similar genes. The genetics of these systems 
are well understood yet informative; interesting al- 
leles exist at these loci that will serve to elucidate 
relationships between the substrate specificities 
and primary structures of glycosyl transferases. More- 
over, these enzymes and their structures are ex- 
pressed in a tissue-specific and developmentally reg- 
ulated manner, and their expression is often altered 
in association with neoplastic transformation. 
To circumvent difficulties associated with con- 
ventional cloning approaches, Dr. Lowe and his col- 
leagues have developed gene transfer strategies to 
isolate glycosyltransferase genes. These strategies 
use existing information about the substrate and ac- 
ceptor properties of these enzymes and take advan- 
tage of antibody and lectin reagents specific for the 
surface-expressed oligosaccharide products of these 
enzymes. Several mammalian glycosyltransferase 
genes have been isolated, including the human H 
blood group locus, a family of a(l,3)fucosyltrans- 
ferase genes that includes the Lewis blood group 
locus, and a murine gene with structural and func- 
tional similarity to the human ABO blood group 
locus. Dr. Lowe's laboratory is continuing to use 
gene transfer approaches to isolate new human and 
mouse glycosyltransferase genes. Ongoing efforts 
are also focused on characterizing murine homo- 
logues of the human genes, in preparation for trans- 
genic animal experiments designed to determine 
the function of their cognate oligosaccharide deter- 
minants during embryogenesis. 
Dr. Lowe and his colleagues have also been inves- 
tigating the roles of cell surface oligosaccharides 
during the inflammatory process. During inflamma- 
tion in humans, neutrophils and monocytes must 
leave their normal locations in the intravascular 
space to arrive at extravascular destinations. The ini- 
tial step involves adhesion between these circulat- 
ing myeloid cells and the protein E-selectin (previ- 
ously known as endothelial leukocyte adhesion 
molecule 1 [ELAM-1]), which is expressed by vascu- 
lar endothelial cells. E-selectin is normally absent 
from quiescent endothelial cell surfaces but is ex- 
pressed prominently in association with inflamma- 
tory stimuli . Like other members of the selectin fam- 
ily of cell adhesion receptors, E-selectin maintains 
an amino-terminal protein domain similar to a con- 
sensus sequence previously defined for C-type 
carbohydrate-binding proteins, or lectins. Although 
it had been suspected that E-selectin mediates adhe- 
sion of neutrophils and monocytes by interacting 
with an oligosaccharide ligand on the surfaces of 
those cells, confirmation of this and the precise na- 
ture of such a ligand had been undefined. By trans- 
fecting various cultured cell lines with specific fu- 
cosyltransferase genes and other glycosyltransferase 
gene segments and cDNAs, Dr. Lowe and his col- 
leagues were able to demonstrate that members of 
the family of a(2,3)sialylated, a(l ,3)fucosylated 
lactosaminoglycans, represented by the sialyl Lewis 
X oligosaccharide determinant, function as ligands 
for E-selectin. 
These observations predicted that these oligosac- 
charides, or their molecular mimics, might prove 
useful as anti-inflammatory pharmaceuticals, by 
blocking adhesion of myeloid cells to E-selectin ex- 
pressed by inflamed endothelium. Two approaches 
that avoid difficulties inherent in chemical synthe- 
sis of oligosaccharides were implemented to create 
oligosaccharides for testing this hypothesis. One 
method uses a recombinant a(l ,3)fucosyltransfer- 
ase for enzyme-assisted in vitro synthesis of the sia- 
lyl Lewis tetrasaccharide. The other method in- 
volves the isolation of sialyl Lewis x-positive 
oligosaccharides from a cultured mammalian cell 
line transfected with an a(l ,3)fucosyltransferase 
gene. Representatives of each of these two types of 
sialyl Lewis x oligosaccharide have been tested re- 
cently, in experiments done in collaboration with 
Dr. Peter Ward and his colleagues (University of 
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