This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality but has an unknown etiology. While the precise pathophysiology is certainly multi-factorial, many investigators believe it represents a microvasculopathy with an important underlying immunopathogenesis. As such, improvements in our understanding of the pathogenesis may provide insights into other vascular disorders. The late onset of symptoms and the myriad conditions associated with its onset have impaired our ability to study this disease. This condition primarily affects humans and the establishment of an animal model has been elusive. The creation of a pre-eclamptic animal model would enhance our understanding of the pathophysiology of pre-eclampsia and contribute to the development of diagnostic, prophylactic and therapeutic modalities needed to combat this disorder. The pre-eclamptic animal model should present some or all of the hallmark features such as placental inflammation, degeneration, intrauterine growth restriction, vascular deficiency, high blood pressure, proteinuria, and kidney pathology. Since pre-eclampsia is a systemic manifestation of local defects at the maternal-fetal interface, we hypothesize that serum from these patients should provide a """"""""blueprint"""""""" of the factors associated with these pathologic conditions. Although there is no precedent for pre-eclampsia serum to manifest any in vivo anomalies, our preliminary data demonstrates that a single injection i.p. of serum on gestational day 10 could induce elevated blood pressure, proteinuria, intrauterine growth restriction, and elevated production of soluble endoglin in wild type C57 Bl/6 mice. In addition, pre-eclampsia serum also disrupted cross talk between trophoblasts and endothelial cells as monitored in a three dimensional culture system on matrigel. To address our central hypothesis and to expand on our preliminary data, we propose the following specific aims.
Specific Aim 1 is designed to assess the in vivo potential of pre-eclampsia serum from mild or severe condition to cause hallmark features of the disease in mice.
In Specific Aim 2, we will determine pre-eclampsia serum-mediated disruption and rescue of cross-talk between extravillous trophoblasts and endothelial cells in an in vitro, three dimensional culture system. These studies will contribute to in vivo and in vitro experimental models to better understand mechanistic underpinnings of and to establish predictive assays for pre-eclampsia.
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