Localizing Maternal and Fetal Message in Translation of Preeclampsia Candidate Ge

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Prevention of the life threatening pregnancy complication preeclampsia is hindered by imprecise knowledge of the molecular etiology of this complex disorder. Current consensus holds that preeclampsia is begins with shallow trophoblast invasion and inadequate remodeling of maternal spiral arteries. A global gene expression microarray analysis of chorionic villus sampling (CVS) specimens obtained at the early stage of pregnancy (11 weeks gestation) in which these events are occurring yielded 36 placental candidate genes in preeclampsia pregnancies. Development and validation of these specific candidates discovered in these early aberrant processes in preeclampsia could represent a tremendous breakthrough. The critical barrier to advancing these 36 candidates is that the quickly snap frozen CVS specimens for our microarray analysis were heterogeneous samples. This impedes our ability to interpret the maternal versus fetal contributions to placentation or pathogenesis. We hypothesize that these 36 candidate genes will be differentially expressed by maternal versus fetal cells at sites of early invasion and spiral artery remodeling. We aim to define these 36 candidate genes by determining maternal versus fetal mRNA expression or both. We will use in situ hybridization in archived first trimester placental sections to localize nd quantify encoded message. We expect the following outcomes from the proposed studies: 1) validated discovery-based candidate genes expressed months before clinical onset of preeclampsia, 2) delineation of tissue types expressing each of the 36 candidate genes at the first trimester maternal-fetal interface, 3) implications for functional relevance of each candidat in first trimester placental development. The positive impact of these outcomes is the improved efficiency of directed translation of our 36 genomic candidates toward clinical utility. Location and relative intensity of candidate gene expression in maternal and/or fetal compartments would inform future studies of genetic/genomic susceptibility and protection, and would hone hypotheses for mechanistic studies of the preeclampsia candidates. These data would inform studies for prevention, early detection, personalized and targeted treatment for preeclampsia. Validated candidates could be relevant to the prediction and early detection of later life preeclampsia-associated cardiovascular disease in mothers and offspring who survive this pregnancy complication.