Document text
Principal Investigator: Lisa Anne Vrooman
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $493,409
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY
There is evidence from human and animal studies that support that imbalance in the renin-angiotensin system
(RAS), specifically reduced ACE2 protein levels and/or activity, leads to adverse maternal and fetal outcomes.
Mouse dams and concepti with loss-of-function alleles of ACE2 exhibit increased embryonic loss, reduced fetal
weight, placental hypoxia, and preeclampsia-like phenotypes in dams. While the RAS has been extensively
studied in the kidney and circulation, much less is known about the local uterine and placental RAS early in
pregnancy and if their disruption contributes to adverse maternal and fetal outcomes. Our proposed collaborative
project will address this need, drawing on my expertise in embryo transfer techniques. The main objective of this
innovative application is to test the hypothesis that ACE2 plays a local role at the maternal-fetal interface
modulating normal placental development and fetal growth independent of the maternal circulating and kidney
RAS. To test this hypothesis, we will conduct in-depth morphological phenotyping, novel RAS protein analyses,
and blood pressure monitoring by radiotelemetry to determine the cell-specific contributions of ACE2 in the
placenta (Aim 1) and decidua (Aim 2). These experiments will elucidate the function of the RAS that are relevant
to idiopathic pregnancy loss and pregnancy complications. Given the known differences between mouse and
human placentas, we will also determine RAS gene expression, protein abundance and localization in rhesus
macaque placentas, which are more structurally similar to human (Aim 3). The Aims outlined in this application
will provide extensive information for the field by improving understanding of the basic RAS function in utero-
placental development during pregnancy. Determining the causes of pregnancy loss, and pregnancy
complications would greatly improve human health, reducing the associated physiological, psychological, and
economic burdens and help us shape advances in maternal-fetal medicine.
Terms: <ACE2><Abnormal placentation><Address><Affect><Alleles><Allelomorphs><Ang I (1-7)><AngII><Angiotensin II><Animals><BP homeostasis><BP regulation><Binding><Biological Function><Biological Process><Biology><Blastosphere><Blood Flow Velocity><Blood Pressure><Blood Pressure Monitors><Blood Serum><Body Tissues><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cells Placenta-Tissue><Circulation><Continuous Sphygmomanometers><Decidua><Decidua Graviditas><Developing fetus><Development><ELISA><EPH Gestosis><Economic Burden><Embryo><Embryo Loss><Embryo Transfer><Embryonic><Endothelial Cells><Enzyme Gene><Enzyme-Linked Immunosorbent Assay><Enzymes><Equilibrium><Exhibits><Fetal Body Weight><Fetal Development><Fetal Growth><Fetal Growth Restriction><Fetal Growth Retardation><Fetal Reduction><Fetal Weight><Fetal health><Fetus><Future><Gene Expression><Generalized Growth><Gestation><Growth><Health><Histologic><Histologically><Histology><Human><Hypoxia><Hypoxic><IUGR><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impairment><Individual><Inflammation><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Investigation><Kidney><Kidney Urinary System><Knock-out><Knockout><Knowledge><Ligands><M mulatta><M. mulatta><Macaca mulatta><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Maternal Health><Maternal-Fetal Exchange><Maternal-fetal medicine><Membrane><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monitor><Morphology><Multifetal Pregnancy Reduction><Murine><Mus><Normal Placentoma><Organ><Outcome><Oxidative Stress><Oxygen Deficiency><Pathway interactions><Pattern><Persons><Phenotype><Physiologic><Physiological><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Play><Pre-Eclampsia><Pre-implantation Embryo Development><Pre-implantation development><Preclinical Testing><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Outcome><Pregnancy Toxemias><Pregnancy loss><Preimplantation Embryo><Preimplantation Embryo Development><Preimplantation development><Proliferating><Protein Analysis><Proteins><Proteinuria-Edema-Hypertension Gestosis><Receptor Protein><Renin-Angiotensin System><Research Proposals><Rhesus Macaque><Rhesus Monkey><Role><SARS-CoV-2 infection><SARS-CoV2 infection><Selective Fetal Terminations><Serum><Severe acute respiratory syndrome coronavirus 2 infection><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Source><Techniques><Testing><Time><Tissue Growth><Tissues><Transgenic Mice><Transplacental Exposure><Umbilical Blood><Uterus><Wild Type Mouse><adverse pregnancy outcome><angiogenesis><angiotensin I (1-7)><angiotensin converting enzyme 2><angiotensin converting enzyme II><angiotensin-(1-7)><balance><balance function><biological signal transduction><blastocyst><blastula><blood pressure elevation><blood pressure homeostasis><blood pressure regulation><complications during pregnancy><coronavirus disease 2019 infection><developmental><disease model><disorder model><elevated blood pressure><embryo transplantation><embryonic loss><enzyme linked immunoassay><experiment><experimental group><experimental research><experimental study><experiments><fetal><human model><impaired fetal growth><improved><in vivo><increase in blood pressure><increased blood pressure><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><innovate><innovation><innovative><intra-uterine growth><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth><intrauterine growth restriction><loss of function><maternal outcome><maternal-fetal interface><membrane structure><model building><model of human><mother outcome><mouse model><murine model><novel><ontogeny><pathway><perinatal outcomes><pre-clinical study><pre-clinical testing><pre-eclamptic><pre-implantation embryo><preclinical study><pregnancy toxemia/hypertension><pregnancy-related complications><pregnant><prenatal growth disorder><psychologic><psychological><receptor><regulate BP><regulate blood pressure><renal><social role><trophoblast><vascular constriction><vasoconstriction><wildtype mouse><womb>