PROCESSING OF HCG IN NORMAL AND ABNORMAL PREGNANCIES

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Preliminary studies in our laboratory are consistent with a relationship between hyperglycosylation (additional antennae and fucose residues on N-linked oligosaccharides) and nicking or cleavage of hCG. Other preliminary studies indicate the structural instability and diminished biological activity of hyperglycosylated and of nicked hCG molecules, and how they may be the source of free beta-subunit in the circulation and beta-core fragment in urine samples. Papers have been published showing raised hCG levels, and raised proportions of free beta-subunit and beta-core fragment levels in serum or urine samples from patients with trophoblast disease, hyperemesis gravidarum, or Down syndrome pregnancies. It is our hypothesis these raised levels arise from the hyperglycosylation of hCG, through pathways involving nicking, ineffectual autocrine control of hCG production, and dissociation to nicked free beta-subunit, and degradation to beta-core fragment. Other pathways raise levels of hCG and lower the proportions of hyperglycosylated hCG in patients with preeclampsia. Four sets of experiments are proposed to test this hypothesis and investigate the clinical ramification of the observations in normal and abnormal pregnancies. Studies are proposed to confirm and compare the levels of hCG, free beta-subunit and beta-core fragment in 1140 sets of parallel serum and urine samples from normal and abnormal pregnancies (Aim 1A); and to use the parallel serum and urine samples to investigate the clinical use of two new immunoassays that specifically measure hyperglycosylated hCG and nicked hCG, and their potential uses in screening for Down syndrome and preeclampsia (Aim 1B). Basic science studies are proposed to purify hCG from normal first, second and third trimester pregnancy urine samples, and preeclampsia, hyperemesis trophoblast disease and Down syndrome pregnancy urine samples (3 each) and compare the extents and sites of nicking, and the type, amounts and locations of hyperglycosylated N-linked oligosaccharides (Aim 2). Further studies are planned to investigate the hyperglycosylation- nicking relationship by comparing normal and hyperglycosylated hCG as substrates for nicking enzymes (Aim 3); and to examine the biological activities of the 21 purified normal and abnormal pregnancy molecules, and to determine their ability abilities to feedback through to the placenta and control hCG synthesis (Aim 4).