Harvey Kliman
Department of Obstetrics and Gynecology
harvey.kliman@yale.edu

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Research
Implantation Research:
Implantation is a major hurdle for successful human reproduction. During most attempts of assisted reproductive technology (ART), fewer than 10% of embryos successfully implant. Abnormalities in the process of implantation may underlie infertility in many women, and undermine the effectiveness of ART. Predictors of implantation potential are needed, both to better understand the causes of infertility in women and to improve the efficacy and reliability of embryo transfer. Despite almost two decades of ART, the precise molecular mediators of human implantation remain unknown. As a corollary to this problem, no molecular markers exist to adequately predict whether implantation will occur during any given ART cycle. My research team hypothesized that the dynamic changes in the endometrium throughout the menstrual cycle require the coordinated expression of specific steroid-modulated molecules. Recently we have identified an epitope on MUC1, the major endometrial mucin, which varies throughout the menstrual cycle. This epitope was first identified in endometrial epithelial cell Golgi because of its strong reactivity with IgG antibodies in numerous murine ascites, hence the designation MAG (mouse ascites Golgi). In donor oocyte recipients, MAG appears on the endometrial surface at the time of embryo transfer in women who ultimately become pregnant, but is absent in donor recipients who fail repeatedly to become pregnant. We have also demonstrated that cyclin E and p27 parallel the normal and abnormal expression of MAG in endometrial biopsies. We are investigating MAG, cyclin E and p27 as markers of endometrial receptivity in order to differentiate implantation-receptive endometrium from non-receptive endometrium in donor oocyte andunexplained infertility patients. The results of these studies should provide new information about the significance of MAG mucin/MUC1, cyclin E and p27 expression in clinical settings where high rates of normal implantation are desired.

Placental Responseto Inflammation:
It is well known that more than a third of all preterm births are associated with labor initiated by acute chorioamnionitis. Not only does chorioamnionitis have severe consequences for the fetus through the initiation of pretermdelivery, but chorioamnionitis is followed by a 20% greater-than-expected frequency of neurologic abnormalities at 7 years of age. Chorioamnionitis appears to be deleterious to the fetus because the inflammatory process induces villous edema. We have hypothesizedthat villous edema makes the fetus hypoxic by compressing fetal blood vessels inside the villi and by increasing the diffusion barrier for oxygen between the maternal and fetal circulations. Our laboratory is developing methods to assess the presence andtiming of villous edema—both pre- and postpartum—and the cytokines responsible for formation of villous edema.

Structural Defects in the Placenta Suggest the Presence of Genetic Defects in the Fetus:
The placenta grows much like a tree. Just as tree growth patterns can be mathematically modeled using fractal equations, the placenta also follows a simple algorithm for its growth. The cellular basis of the placental growth pattern is the dynamic relationship between cytotrophoblast replication and differentiation towards syncytiotrophoblast. We have identified an abnormal growth pattern of the trophoblast layers which appears to be associated with genetic defects in the fetus: trophoblast invaginations. We are collecting histologic datafrom elective andspontaneous terminations, genetic analysis and ultrasound studies to elucidate the correlation between placental structural abnormalities and genetic defects.