CELL ADHESION MECHANISMS IN VASCULAR DISEASE

Support is requested for a new program in vascular biology and medicine
with the goal of advancing the understanding of vascular disease and to
promote the development of new diagnostic and therapeutic strategies.
This will be achieved through the collaborative efforts of a group of
experienced scientists focused on the unifying theme of cell adhesion.
Dr. Ginsberg will study the mechanisms of affinity modulation of
integrins by defining the structures in integrin cytoplasmic domains
which control affinity state and cytoplasmic factors which interact with
them. Integrins in a high affinity state will be expressed in vascular
tissues in transgenic mice to examine potential pathologic roles and to
develop new disease models. The predictive value of spontaneous platelet
activation for negative outcomes in percutaneous transluminal
angioplasty will be analyzed prospectively in patients with coronary
artery disease, and the occurrence of spontaneous variants of alphaIIb
which may lead to platelet activation in the circulation will be
sought. Dr. Swartz will analyze signal transduction from integrins by
defining structural and function requirements for regulation and
transduction systems which control cell growth. As signalling mutants
are identified, they will be expressed in specific tissues of transgenic
mice to examine potential pathogenic properties and they will be
localized in normal and pathological human vascular tissue. Dr. Plow
will evaluate the molecular basis of ligand recognition by the leukocyte
alphaM beta2 and alpha4 beta1 integrins which are involved in leukocyte
localization in the vessel wall. These experiments, using protein-based,
peptide, and recombinant DNA strategies, will define the structural
basis of these interactions, and should provide novel tools to inhibit
leukocyte localization. Dr. Ruggeri will dissect the GPIb binding site
in von Willebrand factor by use of protein, peptide, immunochemical, and
molecular biological approaches. Insights derived from this will be used
to develop novel inhibitors of thrombosis which will be studied in ex
vivo systems and in man. Dr. Loftus will utilize fundamental information
concerning ligand binding domains of integrins to engineer novel gain or
loss of function mutants. The capacity of these mutants, when expressed
in lymphocytes of transgenic mice to induce immunosuppression will be
assessed. Selected mutants will be transfected into endothelial cells as
a potential means to enhance their seeding of vascular surfaces. A
transgenic mouse core under the direction of Dr. Sarvetnick and an in
situ hybridization and histology core under the direction of Drs.
Loskutoff and Bernstein will facilitate the testing of in vitro
hypotheses at the level of the whole animal, and in patients with
cardiovascular disease.