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001-es BibID:BIBFORM078491
035-os BibID:(cikkazonosító)1661 (PMID)30135684 (WoS)000441059500001 (Scopus)85054929775
Első szerző:Than Nándor Gábor (szülész-nőgyógyász)
Cím:Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia / Nandor Gabor Than, Roberto Romero, Adi Laurentiu Tarca, Katalin Adrienna Kekesi, Yi Xu, Zhonghui Xu, Kata Juhasz, Gaurav Bhatti, Ron Joshua Leavitt, Zsolt Gelencser, Janos Palhalmi, Tzu Hung Chung, Balazs Andras Gyorffy, Laszlo Orosz, Amanda Demeter, Anett Szecsi, Eva Hunyadi-Gulyas, Zsuzsanna Darula, Attila Simor, Katalin Eder, Szilvia Szabo, Vanessa Topping, Haidy El-Azzamy, Christopher LaJeunesse, Andrea Balogh, Gabor Szalai, Susan Land, Olga Torok, Zhong Dong, Ilona Kovalszky, Andras Falus, Hamutal Meiri, Sorin Draghici, Sonia S. Hassan, Tinnakorn Chaiworapongsa, Manuel Krispin, Martin Knöfler, Offer Erez, Graham J. Burton, Chong Jai Kim, Gabor Juhasz, Zoltan Papp
Dátum:2018
ISSN:1664-3224
Megjegyzések:Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
preeclampsia
Megjelenés:Frontiers in Immunology. - 9 (2018), p. 1-41. -
További szerzők:Romero, Roberto Tarca, Adi Laurentiu Kékesi Katalin Adrienna Xu, Yi Xu, Zhonghui Juhász Kata Bhatti, Gaurav Leavitt, Ron Joshua Gelencsér Zsolt Pálhalmi János Chung, Tzu Hung Győrffy Balázs Orosz László (1984-) (szülész-nőgyógyász) Demeter Amanda Szécsi Anett Hunyadi-Gulyás Éva Darula Zsuzsanna Simor Attila Eder Katalin Szabó Szilvia Topping Vanessa El-Azzamy, Haidy LaJeunesse, Christopher Balogh Andrea Szalai Gábor Land, Susan Török Olga (1956-) (szülész-nőgyógyász, humángenetikus) Dong, Zhong Kovalszky Ilona Falus András Meiri, Hamutal Draghici, Sorin Hassan, Sonia S. Chaiworapongsa, Tinnakorn Krispin, Manuel Knöfler, Martin Erez, Offer Burton, Graham J. Kim, Chong Jai Juhász Gábor (ELTE) Papp Zoltán (1942-) (szülész-nőgyógyász, genetikus)
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