vous system. The major findings are that specific 
neurite extension activity and neuronal survival ac- 
tivity are two related activities inherent to the 
SlOOp molecule, that a disulfide-linked form of the 
protein is required for full biological activity, and 
that the relative position of the cysteine residues 
can be modified without loss of activity. These data 
suggest potential roles for SIOOP in the develop- 
ment and maintenance of neuronal function in the 
central nervous system and demonstrate the feasi- 
bility of longer term development of selective phar- 
macological agents based on the S 100(3 structure. 
The laboratory of Investigator Joan S. Brugge, 
Ph.D. (University of Pennsylvania) has continued in- 
vestigating the importance of phosphorylation in 
regulating normal cellular events and in inducing 
oncogenic transformation. Structural studies on the 
c-src proto-oncogene product, a prototype protein 
tyrosine kinase, have identified a negative regula- 
tory region outside of the catalytic domain. Muta- 
tional alterations in this region cause an elevation 
in the kinase activity of the src protein and activate 
its ability to alter the growth behaviors and mor- 
phology of cells. The c-src protein expressed in 
neurons contains an insertion of six amino acids 
within this negative regulatory region. Recent stud- 
ies have indicated that this neuron-specific modifi- 
cation elevates the kinase activity of the protein. In- 
vestigations of the role of this protein in neurons 
are under way. The evidence that platelets express 
high levels of the c-src protein tyrosine kinase has 
led Dr. Brugge's laboratory also to examine the role 
of tyrosine phosphorylation in regulating the bio- 
logical activity of platelets. Her studies suggest that 
tyrosine kinases may serve as second messengers in 
mediating events triggered by extracellular cell ad- 
hesion molecules. 
The research interest of the laboratory of Investi- 
gator Charles T. Esmon, Ph.D. (Oklahoma Medical 
Research Foundation) is an understanding of the 
regulation of blood coagulation and the role of the 
clotting system in disease processes. The major ap- 
proaches to these problems involve the protein C 
anticoagulant pathway and the prothrombin activa- 
tion complex. Activated protein C, a vitamin K- 
dependent serine protease, expresses its anticoagu- 
lant activity in part through the inactivation of fac- 
tor Va. Factor Va is a regulatory protein that binds 
to factor Xa, the vitamin K-dependent serine prote- 
ase responsible for prothrombin activation, and ac- 
celerates the rate of prothrombin activation several 
thousandfold. Thus the interplay between the sys- 
tems allows analysis of major regulatory events in 
coagulation. By selectively inhibiting specific com- 
ponents of these systems. Dr. Esmon can analyze 
the role of each pathway in selective disease pro- 
cesses in animal models. 
Associate Investigator J. Evan Sadler, M.D., Ph.D. 
(Washington University) employs DNA cloning and 
biochemical methods to study blood coagulation. 
Many blood clotting proteins are made by the cells 
that line blood vessels or by white blood cells. 
These cells control such proteins to maintain a bal- 
ance between promoting and preventing thrombo- 
sis. This balance is disrupted during inflammatory 
diseases that are associated with blood clots, such 
as bacterial infections. In the past year, three mech- 
anisms were identified that regulate some of these 
proteins, and the structures of the genes for two of 
them were determined. One of these was the von 
Willebrand factor gene. Deletions in this gene were 
characterized in three patients with von Willebrand 
disease, the most common inherited bleeding dis- 
order of humans. 
The laboratory of Assistant Investigator Shaun R. 
Coughlin, M.D., Ph.D. (University of California at 
San Francisco) is pursuing two areas of importance 
in cardiovascular disease. 1) Mechanisms of throm- 
bin action: thrombin is the most potent known ac- 
tivator of platelets, the cells that form plugs in 
blood vessels during blood clotting. Thrombin acti- 
vates platelets by interacting with a "receptor" on 
the platelet surface. The identity of this receptor 
and the way it is activated by thrombin are un- 
known. Dr. Coughlin's laboratory has developed a 
number of novel approaches to identify and clone 
the thrombin receptor and to determine the mech- 
anisms by which it is activated by thrombin. 2) The 
accelerated atherosclerosis of transplants. A rapid 
narrowing of the coronary arteries of transplanted 
hearts is a major cause of transplant failure. On the 
premise that accelerated transplant atherosclerosis 
represents an interaction of the recipient's immune 
system with the growth factor systems governing 
the proliferation of cells in arterial walls. Dr. 
Coughlin's laboratory, in collaboration with others, 
is identifying the immune cell types, growth factors, 
and growth factor receptors that are present during 
the development of transplant atherosclerosis in a 
rat model. 
Investigator H. Franklin Bunn, M.D. (Brigham 
and Women's Hospital) and his colleagues have 
been investigating the gene for the hormone eryth- 
ropoietin, which stimulates the formation of red 
blood cells. They have shown that exposure of 
erythropoietin-producing cells to low oxygen ten- 
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