Document text
Principal Investigator: Peixin Yang
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2023
Award: $400,000
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><4 hydroxynonenal><4-HNE cpd><4-hydroxy-2,3-nonenal><4-hydroxy-2-nonenal><4-hydroxynonen-2-al><ACE2><Abdominal Delivery><Acquired brain injury><Address><Apoptosis><Apoptosis Pathway><Asthma><Autolyses><Autolysis><Autophagocytosis><Biological><Body Tissues><Brain Injuries><Bronchial Asthma><C section><COVID><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 diagnosis><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 diagnosis><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cancers><Causality><Cell Body><Cell Communication and Signaling><Cell Death><Cell Fate Control><Cell Fate Regulation><Cell Signaling><Cells><Cells Placenta-Tissue><Cellular injury><Cesarean><Cesarean section><Chronic><Clinical><CoV disease><CoV-2><CoV2><Detection><Development><Disease><Disorder><Dysfunction><EPH Gestosis><Endocrine Gland Secretion><Etiology><Event><Fe element><Fe metabolism><Fetal Growth Restriction><Fetal Growth Retardation><Formalin><Functional disorder><Gene Expression><Gestation><Glycoproteins><Heart Injuries><Hormones><Human><IUGR><Immunofluorescence><Immunofluorescence Immunologic><In Situ Hybridization><In Vitro><Individual><Infection><Inflammation><Injury><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Iron><Knowledge><Link><Lipid Peroxidation><Malignant Neoplasms><Malignant Tumor><Malonaldehyde><Malondialdehyde><Malonylaldehyde><Malonyldialdehyde><Mission><Modern Man><Molecular><Mononuclear><NIH><National Institutes of Health><Necrosis><Necrotic><Neonatal><Non-Polyadenylated RNA><Normal Placentoma><Nucleocapsid><Outcome><Ovarian><Oxidation-Reduction><Oxidative Stress><Paraffin Embedding><Pathogenesis><Pathology><Pathway interactions><Phosphatides><Phospholipids><Physiologic><Physiological><Physiology><Physiopathology><Placenta><Placenta Embryonic Tissue><Placentome><Play><Polyunsaturated Fatty Acids><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Rate><Pregnancy Toxemias><Pregnant Women><Preventive><Process><Programmed Cell Death><Propanedial><Proteinuria-Edema-Hypertension Gestosis><Public Health><RNA><RNA Gene Products><RNA Viruses><Receptor Protein><Redox><Regulation><Reporting><Research><Ribonucleic Acid><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 diagnosis><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Staining method><Stains><Syncytiotrophoblast><Therapeutic Hormone><Therapeutic Intervention><Tissues><Trophoblastic Cell><United States National Institutes of Health><Uterus><Viral Diseases><Viral Genome><Virion><Virus Diseases><Virus Particle><Wuhan coronavirus><adverse pregnancy outcome><angiotensin converting enzyme 2><angiotensin converting enzyme II><autophagy><biologic><biological signal transduction><brain damage><brain-injured><cardiac injury><causation><cell autolysis><cell damage><cell injury><cellular damage><complications during pregnancy><corona virus disease><corona virus disease 2019><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 diagnosis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><cytotrophoblast><damage to cells><developmental><diabetic embryopathy><diagnosed with COVID-19><diagnosed with COVID19><diagnosed with SARS-CoV-2><diagnosed with coronavirus 2019><diagnosed with coronavirus disease 2019><disease causation><expectant mother><expecting mother><experience><fetal><hCoV19><histiocyte><human disease><impaired fetal growth><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vitro Model><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injuries><injury to cells><intervention therapy><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><iron metabolism><malignancy><mammary><nCoV2><necrocytosis><neonate><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><obstetric outcomes><obstetrical complication><oxidation reduction reaction><paraform><paraformaldehyde><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with 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infection><virus-induced disease><womb>