Date of Graduation

5-2016

Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Yang Xia, MD/PhD

Committee Member

Rodney Kellems, PhD

Committee Member

Dorothy Lewis, PhD

Committee Member

Sandeep Agarwal, MD/PhD

Committee Member

Jeffrey Actor, PhD

Abstract

Preeclampsia (PE) is a severe, acute disease of pregnancy affecting approximately 8% of pregnant women after week 20 of gestation. PE is characterized by hypertension and renal damage reflected by proteinuria and has significant morbidity to both mother and fetus. Maternal symptoms range from headaches, nausea, edema, to visual changes, but once maternal symptoms present, damage to the fetus has begun. Mothers who progress untreated through the disease can also experience a condition called eclampsia characterized by seizure, coma, and, ultimately, death. PE-affected newborns experience features similar to prematurity—abnormal lung and renal development, intrauterine growth retardation (IUGR), and, possibly, fetal demise. Interestingly, it has been shown that exposure to PE in utero can lead to many developmental problems during the progeny’s life span. While intensive research has been dedicated to understanding the underlying pathogenesis of PE, no cause, predictive clinical test, nor definitive treatment has been discovered.

Although many factors are presumed as causative for PE pathogenesis, literature has indicated that acute inflammation may play a role in the development of PE. One such inflammatory factor is C-reactive protein (CRP). CRP, although regarded as a non-specific innate immune factor, is found to be elevated in PE mothers prior to onset of symptoms. The presence could indicate that CRP mayplay a role in the development of PE pathology. Further, CRP binds to bacterial membranes through phosphocholine residues to trigger complement and other innate immune responses.

Similarly, phosphocholination is a cellular process wherein phosphocholine residues are added to biological molecules via an endoplasmic reticularly mediated enzyme, phosphocholine transferase. A recently identified neurally- secreted placental peptide and known pathogenic factor of PE, Neurokinin B (NKB), is phosphocholinated. This post-translational phosphocholination is thought to increase stability and binding of NKB to its Gq coupled receptor, NK3R. It is thought that this post-translational modification is bound by CRP thereby creating a molecular complex to preferentially activate NK3R.

In addition to investigating the pathogenic role of inflammation in PE, we are also curious as to how intrauterine expose to PE affects cardiovascular development in progeny. Previous literature has demonstrated that PE predisposes offspring to adult-onset hypertension; however, the mechanism of this fetal programing remains unknown. We hypothesize that hypertension in offspring exposed to PE in utero results via a two hit mechanism: 1) PE-related intrauterine stress induces epigenetic modifications in offspring, and 2) these modifications in the presence of environmental stressor lead to hypertension. Furthermore, we postulate that these epigenetic modifications are conserved across generations. Intrauterine epigenetic changes, specifically decreased global methylation of renal DNA and AT1R promoter, in offspring born to PE mothers are conserved across generations. When combined with an additional environmental stimulus, these changes result in hypertension. These finding posit novel mechanisms for the etiology of hypertension and provide vital screening targets to assess the risk of hypertension in progeny.

These two approaches to PE study combine investigation of the maternal PE insult and pathogenesis with the investigation of transgenerational hypertensive features to progeny, we posit a global view of PE study. We not only examine potential targets for therapeutics and preclinical diagnostic exams, we also provide a mechanism for transmission of hypertensive features through generations and the possibility for hypertensive risk assessment.

Keywords

Hypertension, Inflammation, Epigenetics, Preeclampsia, Pregnancy

Available for download on Friday, May 05, 2017

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