Preeclampsia (PE) is a high incidence pregnancy-specific syndrome and a leading cause of maternal and neonatal mortality. PE is diagnosed by the sudden onset of hypertension, proteinuria, thrombosis, and placental abnormalities. While PE has been clinically recognized and diagnosed for decades, the mechanisms that trigger its pathogenesis remain poorly understood. Others and we have recently shown that PE is characterized by the presence of maternal autoantibodies capable of activating the angiotensin receptor (AT 1R). Our preliminary data indicate that AT1 agonistic autoantibodies (termed AT1-AA) activate AT1R on a variety of cell types and provoke biological responses that are relevant to the pathophysiology of PE. Intriguingly, AT1-AA is consistently directed against a seven amino acid (7- AA) epitope associated with the second extracellular loop of the AT1R. Computer analysis revealed a sequence homology between capsid proteins VP1 and VP2 of human parvovirus B19 (HPV B19) and the 7-AA AT1R epitope peptide, implying that molecular mimicry between HPV B 19 and AT 1R may underlie the mechanistic origins of AT1- AA. Collectively our preliminary findings suggest that the AT1-AA contribute to the pathophysiology of PE. Therefore, our long-range goal is to evaluate the contributions of AT1-AA to PE and explore the immunological origins of these autoantibodies. To address this goal I have organized three specific aims: (I) evaluate the pathophysiological role of AT1-AA in animal models. We shall determine whether the features of PE can be adoptively transferred to mice by the introduction of AT1-AA and by immunization with the 7-AA epitope peptide of the AT1R in mice. (II) Develop improved methods for conveniently and accurately quantifying AT1-AA. We propose to develop improved biological assays and efficient immunochemical assays to quantify AT1-AA. (III) Determine whether molecular mimicry between Human Parvovirus B 19 capsid proteins and AT1 receptors underlies the immunological origin of AT1-AA. Initially, we shall evaluate the association of PE with previous HPV B19 infection. If they are associated, we will further test the possibility of molecular mimicry between HPV B 19 and AT 1R by both in vitro and in vivo experiments. In summary, we have obtained considerable preliminary data supporting the hypothesis that PE is characterized by the presence of maternal autoantibodies capable of activating AT1R. This hypothesis has the ability to explain many features of this complex life threatening condition and immediately suggests diagnostic and therapeutic opportunities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076558-04
Application #
7365238
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Barouch, Winifred
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2010-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$246,409
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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Wang, Wei; Parchim, Nicholas F; Iriyama, Takayuki et al. (2014) Excess LIGHT contributes to placental impairment, increased secretion of vasoactive factors, hypertension, and proteinuria in preeclampsia. Hypertension 63:595-606
Siddiqui, Athar H; Irani, Roxanna A; Zhang, Weiru et al. (2013) Angiotensin receptor agonistic autoantibody-mediated soluble fms-like tyrosine kinase-1 induction contributes to impaired adrenal vasculature and decreased aldosterone production in preeclampsia. Hypertension 61:472-9

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