Dr. McCrae has recently completed his clinical training in hematology, and been appointed Assistant Professor of Medicine at the University of Pennsylvania. He is applying for a clinical Investigator Award, which would allow him the unique opportunity to obtain additional research training in the field of reproductive biology. During the last three years of his fellowship training, the majority of Dr. McCrae's effort was spent in Dr. Douglas Cines' laboratory, where he studied antibody-mediated endothelial damage, as well as interactions of endothelial cells with the plasminogen activator (PA) system. He now wishes to apply the knowledge he has obtained in previous studies to the field of reproductive biology, and the study of a new cell, the trophoblast. His recent appointment will allow him to devote approximately 90% of his time to research. He seeks funding to support this work, which will entirely devoted to the project outlined in this proposal. Establishment of an adequate placental vasculature is vital for normal growth and development of the fetus. The success of this process depends upon the ability of cytotrophoblasts to invade and remodel uterine spiral arteries, and to form the trophoblast-lined uteroplacental arteries, which carry maternal blood to the placenta. The ability of trophoblasts to invade and remodel maternal decidual and vascular tissues and maintain blood fluidity in remodeled vessels may depend on their regulated production of urokinase-type plasminogen activator (uPA), uPA receptors (UPAR) and plasminogen activator inhibitors (PAis). Placental insufficiency and infarction may occur when these PA-dependent processes are disrupted. Dr. McCrae proposes to study the production and expression of uPA, PAis and uPAR by trophoblasts isolated from the placentae of normal pregnant women. The effect of specific cytokines on the production and expression of these proteins by trophoblasts will be determined. He will then perform similar studies using trophoblasts isolated from the placentae of women with systemic lupus erythematosus, antiphospholipid antibodies and preeclampsia--three diseases in which deficient trophoblast-mediated PA activity may result in inadequate placentation and subsequent placental ischemia. Finally, Dr. McCrae will determine the incidence of anti- trophoblast antibodies in the plasma of these patients, and measure the effects of such antibodies on the expression of PA activity by trophoblasts isolated from the placentae of normal pregnant women. Dr. McCrae's current environment is ideally suited to support his continued career development. All the capital equipment for performing these studies is readily available. Dr. McCrae's sponsors, Drs. Douglas Cines and Jerome Strauss, have had extensive experience in assisting young investigators develop independent careers in laboratory investigation, and have scientific expertise in the areas which Dr. McCrae proposes to study. Dr. McCrae will have ample opportunity to further his basic science knowledge by participating in seminars, courses and research conferences held throughout the University of Pennsylvania. He will also have the unique opportunity to expand his knowledge of the field of reproductive biology, by attending conferences and interacting closely with members of the Division of Reproductive Medicine.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Maternal and Child Health Research Committee (HDMC)
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University of Pennsylvania
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Multhaupt, H A; Mazar, A; Cines, D B et al. (1994) Expression of urokinase receptors by human trophoblast. A histochemical and ultrastructural analysis. Lab Invest 71:392-400
Samuels, P; Steinfeld, J D; Braitman, L E et al. (1993) Plasma concentration of endothelin-1 in women with cocaine-associated pregnancy complications. Am J Obstet Gynecol 168:528-33
McCrae, K R; DeMichele, A M; Pandhi, P et al. (1993) Detection of antitrophoblast antibodies in the sera of patients with anticardiolipin antibodies and fetal loss. Blood 82:2730-41
McCrae, K R; Samuels, P; Schreiber, A D (1992) Pregnancy-associated thrombocytopenia: pathogenesis and management. Blood 80:2697-714
Zini, J M; Murray, S C; Graham, C H et al. (1992) Characterization of urokinase receptor expression by human placental trophoblasts. Blood 79:2917-29