in this laboratory are centered largely on structure/ 
function analysis. Initial work has focused on the 
reactive center of PAI- 1 . 
A large library of mutants has been constructed, 
containing all possible sequences at the PI and PI' 
residues. Analysis of 340 mutants to date has identi- 
fied a requirement for either Arg or Lys at PI for 
activity against uPA. The PI' position appears to be 
tolerant of a wide range of amino acid substitutions, 
with the exception of Pro. Several of these novel 
reactive center variants demonstrate remarkable tar- 
get specificity for uPA over tPA. Recently a new class 
of mutants has been identified with residues other 
than Lys or Arg at P 1 , which maintain selective inhib- 
itory activity against tPA, with no detectable activity 
for uPA. In other studies, chimeric SERPIN mole- 
cules are being constructed, combining the amino 
terminus of a, -antitrypsin or antithrombin III with 
the carboxyl terminus of PAI-1. By this approach, 
regions critical for the interaction of PAI- 1 with vi- 
tronectin and heparin have been identified. 
The laboratory has recently characterized the mo- 
lecular defect in a patient with a hereditary bleeding 
disorder associated with low PAI-1 levels. She is ho- 
mozygous for a 2-bp insertion in exon 4, resulting in 
complete loss of functional PAI-1 expression. Sur- 
prisingly, she demonstrates no obvious clinical ab- 
normalities, aside from her moderate bleeding dis- 
order. In addition to identifying the molecular basis 
for a new human bleeding disorder, these observa- 
tions have important implications for the role of 
PAI- 1 in vivo. Genetic analysis of additional patients 
with PAI-1 deficiency is in progress. This work has 
been supported in part by a grant from the National 
Institutes of Health. 
Bone Marrow Transplantation 
Currently the major obstacle to the more wide- 
spread use of bone marrow transplantation (BMT ) to 
treat human disease is an often fatal complication 
called graft-versus-host disease (GVHD). GVHD 
does not occur in BMT between identical twins but 
is a frequent complication when bone marrow is 
used from a nonidentical but HLA-matched sibling. 
Thus one or more genetic loci outside of the HLA 
complex appear to be critical determinants of 
GVHD. Dr. Ginsburg has recently begun a new re- 
search program, attempting to identify these loci by 
a "genome scan" analysis of highly polymorphic 
microsatellite markers. If this effort is successful, 
the identified markers will find immediate applica- 
tion in the refinement of the BMT-matching proce- 
dure. In addition, identification of the actual ge- 
netic loci should open important avenues for future 
research. 
Dr. Ginsburg is also Associate Professor of In- 
ternal Medicine and Human Genetics at the Uni- 
versity of Michigan Medical School. 
Books and Chapters of Books 
Bahou, W., Bockenstedt, P., and Ginsburg, D. 
1992. Hemophilia and allied disorders. In Princi- 
ples and Practice of Emergency Medicine 
(Schwartz, G.R., Cayten, C.G., Mangelsen, M.A., 
Mayer, T.A., and Hanke, B.K., Eds.). Philadelphia, 
PA: Lea & Febiger, vol II, 3rd ed, pp 1998-2006. 
Articles 
Cooney, K.A., Lyons, S.E., and Ginsburg, D. 1992. 
Functional analysis of a type IIB von Willebrand 
disease missense mutation: increased binding of 
large von Willebrand factor multimers to plate- 
lets. Proc Natl Acad Sci USA 89:2869-2872. 
Ginsburg, D., Bockenstedt, P.L., Allen, E.A., Fox, 
D.A., Foster, P.A., Ruggeri, Z.M., Zimmerman, 
T.S., Montgomery, R.R., Bahou, W.F., Johnson, 
T.A., and Yang, A.Y. 1992. Fine mapping of 
monoclonal antibody epitopes on human von 
Willebrand factor using a recombinant peptide li- 
brary. Thromb Haemost 67:166-171 . 
Ginsburg, D., and Bowie, E.J.W. 1992. Molecular 
genetics of von Willebrand disease. Blood 
79:2507-2519. 
Lyons, S.E., Bruck, M.E., Bowie, E.J.W. , and Gins- 
burg, D. 1992. Impaired intracellular transport 
produced by a subset of type HA von Willebrand 
disease mutations. /^?o/ Chem 267:4424-4430. 
Roth, M.S., Antin, J.H., Ash, R., Terry, V.H., Got- 
lieb, M., Silver, S.M., and Ginsburg, D. 1992. 
Prognostic significance of Philadelphia chromo- 
some-positive cells detected by the polymerase 
chain reaction after allogeneic bone marrow 
transplant for chronic myelogenous leukemia. 
5/00^/79:276-282. 
Sherman, P.M., Lawrence, D.A., Yang, A.Y., Van- 
denberg, E.T., Paielli, D., Olson, S.T., Shore, J. D., 
and Ginsburg, D. 1992. Saturation mutagenesis 
of the plasminogen activator inhibitor- 1 reactive 
center, f Biol Chem 267:7588-7595. 
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