Autophagy and its Regulation in Diabetic Embryopathy

University Of Maryland Baltimore, Baltimore MD

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Abstract

SARS-CoV-2 infection induces activation of ferroptosis in the placenta Summary Pregnancy is a risk factor for SARS-CoV-2 infection and worse COVID-19 outcomes. Therefore, there is an urgent need for research into underlying mechanisms leading to the pathogenesis of adverse pregnancy outcomes and the development of optimal COVID-19 treatment during pregnancy. Most adverse pregnancy outcomes are of placental origin because the human placenta can synthesize many hormones and cytokines to influence ovarian, uterine, mammary, and fetal physiology. Recent advances in understanding cell death mechanisms in cell death mechanisms have led to significant recognition of the role of ferroptosis in regulating cell fate. As a form of nonapoptotic programmed cell death, ferroptosis is characterized by redox-active iron- dependent hydroxy-peroxidation of polyunsaturated fatty acid-containing phospholipids and compromised lipid peroxidation repair capacity. Because dysregulation of iron metabolism plays has been shown to play an important role in the etiology of COVID-19, the central hypothesis of this study is that SARS-CoV-2 infection leads to activation of the ferroptosis process in the placenta, thereby serving as a pivotal contributor to dysregulation of placental function and subsequently pathogenesis of adverse pregnancy outcomes. We plan to pursue two Aims. Aim 1. To determine gene expression levels of hallmarks of ferroptosis in SARS-CoV-2-infected human primary placental tissues and trophoblastic cells. A number of studies have shown increased COVID-19 risk among pregnant women experiencing obstetrical complications. While multiple underlying signaling pathways may associate these two events, we hypothesize that ferroptosis is primarily responsible. Aim 2. To recapitulate SARS-CoV-2 infection-induced activation of the ferroptosis process in the placenta in vitro. We will use human primary placental cytotrophoblast as an in vitro model to accomplish this Aim. This research is significant because it addresses a fundamental question regarding mechanisms underlying correlation of COVID-19 and pathogenesis of adverse clinical outcomes. Furthermore, this study explores a novel concept: ferroptosis signaling can serve as such a mechanism, thus facilitating development of new and effective therapeutic approaches for treatment of these complications.