Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Translational Biomedicine

First Advisor

Allyn Mark

Abstract

Preeclampsia is a hypertensive disorder of pregnancy that is diagnosed after the 20th week of gestation. It is defined by the American College of Obstetrics and Gynecology as de novo hypertension of at least 140/90 in a pregnant woman. Proteinuria with the hypertension is sufficient but not required for the diagnosis, especially if a woman displays severe symptoms such as headache, blurry vision, right upper quadrant pain, and low platelet count. Despite significant research, preeclampsia continues to kill 76,000 mothers and 500,000 babies per year worldwide. It causes short and long term consequences such as future metabolic and cardiovascular events for the mother and the child born during a pregnancy affected by preeclampsia. A delay in diagnosis and delayed access to appropriate care is a core cause of the preeclampsia related morbidity and severe mortality worldwide. Despite being in the medical literature since the time of the ancient Greeks, there is currently no significant predictive, preventative, therapeutic, and curative agent for preeclampsia except for an often preterm delivery of the fetus. The complex pathogenesis of preeclampsia has challenged the ability to effectively predict preeclampsia to decrease the delay in this diagnosis. Consequently, an early intervention or triage to higher level obstetric care is hindered. The lack of an early biomarker for preeclampsia also represents a major barrier to treat preeclampsia before major clinical symptoms emerge and the cycle of future cardiovascular risk for mom and baby begins. Novel, very early pregnancy predictive tests for preeclampsia may provide significant clinical utility. Furthermore, a biomarker that is linked with an early pathogenic mechanism in the first trimester development of preeclampsia would reveal a new avenue of early, first trimester intervention to treat and prevent this devastating disease.

This work details the search for such a biomarker linked to an early initiator of the molecular pathogenesis of preeclampsia. These microRNA data highlight very important dysregulated mechanisms including immunologic, cell growth, and angiogenic mechanisms. T cells and the role of indoleamine 2,3 dioxygenase (IDO) is important in the early, maternal immune tolerance to the placenta and pregnancy. As poor placentation is a core cause of preeclampsia, a decreased immune tolerance to it is hypothesized to lead to preeclampsia. Furthermore, low IDO activity has been observed in the placentas of preeclamptic pregnancies which may make it a viable biomarker. These IDO-knock out mouse data, demonstrate that chronic IDO deficiency is sufficient to cause some of the core phenotypes of preeclampsia including renal dysfunction, vascular endothelial dysfunction, fetal growth restriction, and a slight increase in systolic blood pressure. This model does not completely phenocopy human preeclampsia. An investigation of early markers that are linked to vascular, immune, and renal abnormalities highlights the vasopressin pathway as a potential biomarker and early initiator of the pathogenesis of preeclampsia. These data demonstrate that copeptin, as a stable marker of vasopressin secretion, is robustly predictive of the development of late pregnancy human preeclampsia, as early as the 6th week of gestation. Furthermore, a mouse model with chronic infusion of vasopressin throughout mouse gestation phenocopies all the essential aspects of human preeclampsia: pregnancy specific hypertension, proteinuria, pathognomonic glomerular endotheliosis, fetal growth restriction, and increased fetal death. Further research must be done to elucidate the immunologic, vascular, and fetal programming phenotypes of this model. This work posits the possibility that the vasopressin pathway may provide new predictive, preventative, therapeutic, and potentially curative modalities for preeclampsia.

Public Abstract

Preeclampsia (PE) is a high blood pressure disorder that often occurs at the end of pregnancy. It is defined by new high blood pressure in a pregnant woman. An increased level of protein in the urine may or may not accompany variable symptoms, such as headache, blurry vision, and/or abdominal pain. This broad clinical picture causes a delayed diagnosis which can cause an increase in complications for the mother and the baby. The ability to predict, prevent, and cure preeclampsia is hindered by a lack of understanding of the early causes of this disease. Consequently, every minute a mother or baby dies due to preeclampsia related problems. This work details the search for a reliable, early predictor of preeclampsia that is linked to its early mechanisms. These data also suggest that the pathway of a brain hormone, vasopressin, may provide such a predictor. An early pregnancy predictor of preeclampsia that is part of its earliest mechanisms would be an important tool in developing prediction strategies, early prevention options, and a possible cure for this devastating disease.

Keywords

publicabstract, Animal Model, Biomarker, Early Prediction, First Trimester, Pathogenesis, Preeclampsia

Pages

xii, 169 pages

Bibliography

Includes bibliographical references (pages 126-169).

Copyright

Copyright 2016 Mark K. Santillan

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