Chemistry and Biochemistry

Graves Research Lab

The sodium pump and its inhibitors in disease

Research on the role of the sodium pump in disease touches on two broad areas. The first involves the study of high blood pressure (hypertension) in pregnant women who develop preeclampsia, a life-threatening, hypertensive complication of pregnancy. My studies have previously addressed the regulation of cations in the context of hypertension. We have given special emphasis to the isolation and detailed characterization of a putative hormone known as the digitalis-like factor (DLF) which appears to have a role in patients with preeclampsia. Its concentrations correlate with blood pressure and the isolated factor causes contraction of blood vessels (the abnormality most commonly responsible for increased blood pressure) at very low concentrations, consistent with its being a regulatory factor and having a role in hypertensive disease. DLF acts specifically on an important cell membrane protein complex termed the sodium pump or [Na,K]ATPase as an inhibitor. Projects assess the mechanism of action of this compound, its regulation by other hormones or physical stimuli, its biosynthetic pathway, its detailed chemical structure, as well as further studies into its participation in other diseases, in particular cataracts.

The second area of research on the sodium pump involves the expression of sodium pump isoforms in the cell membrane of individuals, both as part of normal physiology and as part of pathology. We will study the translational and transcriptional regulation of the sodium pump isoforms to explain their unique distribution in different tissues and modifications in distribution. Our previous studies have demonstrated changes in the sodium pump in women with preeclampsia. Some projects will be focused on changes in the sodium pump isoform distribution in women with hypertensive complications of pregnancy. Another set of projects study the sodium pump isoform distribution and changes in the lens and the possible role of sodium pump isoform changes in the formation of cataracts, where the sodium pump appears to be reduced which alteration gives rise to the features of the disease itself.

The sodium pump and mechanisms in labor

We have exciting data to suggest that the sodium pump may play a fundamental role in the progression of both human and mouse labor and delivery. Recently, we demonstrated that there are reductions in a selected isoform of the sodium pump in the placenta and uterus of women who are in labor compared with pregnant women not in labor. The reduction of this sodium pump isoform in the placenta is predicted to increase the release of paracrine factors that may initiate labor or contribute to its progression. The reduction of this sodium pump isoform in the uterus would bring about stronger, longer and more frequent contractions and may explain the progression of labor. Similar changes occur in the pregnant mouse. Additionally, induction of labor in pregnant preterm mice, is also attended by reductions in one isoform of the sodium pump, a change that would cause uterine contractions to be longer, stronger and more frequent. We are interested in knowing what the mechanism is for this reduction in the one sodium pump isoform. Current work suggests that changes in mRNA are responsible for changes in the uterine abundance of the sodium pump isoforms seen in term pregnancy. However, a different mechanism appears to be involved in their regulation in the placenta. We are interested then in knowing what regulates the changes in transcription in the uterus and what the mechanisms are for reductions in the placenta independent of mRNA. We have also studied the changes in sodium pump isoforms in uterus and placenta in preterm animals who have labor induced. Here we have also found reductions in sodium pump isoforms which occur too quickly to be mediated by transcription and translation. We are currently working to determine how these changes are brought about.

Proteomics of preterm birth and preeclampsia

Over the past several months I in conjunction with collaborators at the University of Utah Medical School have begun exploring differences in serum peptides and proteins in pregnant women who experience complications in their pregnancies compared with pregnant women with uncomplicated pregnancies. Current research suggests that there are differences between women who go on to have a preterm delivery and those who do not. These changes occur weeks to months before the clinical problem. We are actively identifying what these proteomic factors are, not only to help predict women at risk for preterm birth but also to evaluate these molecules as potential mediators of the disease. Others studies have explored the serum proteome in preeclamptic women and have also identified differences between women with or who will have preeclampsia and pregnant women who have uncomplicated pregnancies. Some of these studies suggest that there are observable alterations in several molecular species that pre-date clinical signs and symptoms of preeclampsia by many weeks. The prognostic value of such findings if validated would be enormous. Of greater interest to us is knowing what role these factors may have in the progression of the disease. Current projects assess changes in the serum proteome that occur as a woman nears the end of her pregnancy as well as to carry out detailed studies of preterm birth prediction, preeclampsia prediction and studies to identify candidate peptides and proteins that mediate these events.