Document text
Principal Investigator: Ryan Lynn Ashley
Organization: NEW MEXICO STATE UNIVERSITY LAS CRUCES
Fiscal Year: 2024
Award: $370,000
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
Impaired placental function leads to dangerous pregnancy complications such as preeclampsia, intrauterine
growth restriction, placental abruption, and stillbirth. Placental dysfunction is the leading cause of maternal,
fetal, and neonatal morbidity and mortality worldwide and predisposes offspring to higher risks of developing
cardiovascular disease, type 2 diabetes, insulin resistance, obesity, hypertension, and stroke during
adulthood. To improve human health, it is imperative to elucidate the mechanisms causing impaired placental
development. The chemokine, CXCL12 (L12) regulates several processes central to the development of the
placenta (placentation) such as stimulating cell proliferation and migration, vascularization, immune cell
recruitment and cytokine production through direct actions on fetal trophoblast and maternal endometrial and
immune cells. These essential functions are elicited via L12 activating its two receptors, CXCR4 (R4) and/or
CXCR7 (R7); however, the contributions of R4 compared to R7 during placentation remain unclear, denoting a
substantial gap in knowledge. Our group and others demonstrated L12-mediated signaling is strongly
implicated in placental dysfunction and specifically preeclampsia etiology. Defining L12-induced actions
through its two receptors may reveal underlying mechanisms causing placental dysfunction. We developed an
innovative animal model to study L12-dependent signaling at the fetal (trophoblast)-maternal (endometrial)
interface by delivering treatments directly into the uterus. Our published and preliminary data demonstrate
disrupting L12-mediated signaling during the small window of embryo implantation diminishes placental
vascularization, induces autophagy, and creates an excessive inflammatory placental environment later in
gestation. Notably, several observed outcomes mirror those of placental dysfunction, suggesting an imbalance
in L12/R4/R7 signaling may be causative. Preliminary data indicate transitory suppression of L12/R4 signaling
induces lasting placental insufficiency with preeclampsia markers VEGF receptor-1 (sFLT-1) and placental
growth factor (PlGF) remaining elevated months later, at midgestation. Whether excessive R7 activation
contributes to these findings when R4 is suppressed remains uncertain. Our data underscore the importance
of L12 during placentation and provide strong evidence that altering L12-mediated signaling induces enduring
placental effects manifesting later in gestation. Nevertheless, we lack a clear understanding of how L12,
excreted by fetal trophoblast cells, signals through R4 and R7 on trophoblast and maternal cells. This SC1 will
test the overall hypothesize that L12 induces distinct biological responses through R4 versus R7, thereby
differentially impacting placental development, function, and fetal growth. Results from Aim 1 will provide new
scientific knowledge on R4 and R7 functions in placental biology during times impractical to obtain in humans
through characterizing a robust in vivo model and placental phenotype at select gestational times. Mechanistic
in vitro studies in Aim 2 will delineate L12-mediated signaling in fetal and maternal cells.
Terms: <21+ years old><AMD-3100><AMD3100><Abruptio Placentae><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Amniotic Fluid><Animal Model><Animal Models and Related Studies><Apoplexy><Aqua Amnii><Autophagocytosis><Biological><Blastocyst Implantation><Blood Plasma><Blood Pressure><Brain Vascular Accident><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CXC-R4><CXCL12><CXCL12 gene><CXCL12 protein><CXCR><CXCR-4><CXCR4><CXCR4 gene><Cardiovascular Diseases><Cas nuclease technology><Causality><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell Survival><Cell Viability><Cells><Cells Placenta-Tissue><Cellular Migration><Cellular Motility><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemokine (C-X-C Motif) Ligand 12><Chemotactic Cytokines><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Comprehension><D2S201E><Dangerousness><Data><Dissection><Dysfunction><EPH Gestosis><Embryo Implantation><Endometrial><Environment><Etiology><Event><Excretory function><FB22><FLK1><Fetal Growth><Fetal Growth Restriction><Fetal Growth Retardation><Fetal health><Foundations><Functional disorder><Funding><Generalized Growth><Generations><Gestation><Growth><Growth Agents><Growth Factor><Growth Substances><HM89><HSY3RR><Health><Homologous Chemotactic Cytokines><Human><Hypertension><IUGR><Immune><Immunes><Impairment><In Vitro><Inflammatory><Insulin Resistance><Intercrines><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Invaded><KDR gene><Ketosis-Resistant Diabetes Mellitus><Knowledge><LAP3><LCR1><LESTR><Liquor Amnii><Maternal-Fetal Exchange><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Methods><Mitogenesis><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><NIDDM><NIH><NPY3R><NPYR><NPYRL><NPYY3R><National Institutes of Health><Neonatal Mortality><Nidation><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Normal Placentoma><Obesity><Outcome><Ovum Implantation><PBSF><PGF gene><PLGF-2><Pathogenesis><Pathologic><Pathology><Perfusion><Pharmacological Treatment><Phenotype><Physiopathology><PlGF><PlGF protein><Placenta><Placenta Biology><Placenta Embryonic Tissue><Placental Biology><Placental Development><Placental Growth Factor><Placental Insufficiency><Placentation><Placentome><Plasma><Plasma Serum><Play><Plerixafor><Position><Positioning Attribute><Positive Control of Cell Proliferation><Pre-B Cell Growth Stimulating Factor><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Toxemias><Premature Separation of Placenta><Process><Production><Productivity><Proliferating><Proteins Growth Factors><Proteinuria-Edema-Hypertension Gestosis><Proteome><Publications><Publishing><Receptor Protein><Regulation><Research><Reticuloendothelial System, Serum, Plasma><Role><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><SIS cytokines><Scientific Publication><Sdf1 protein><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Solid><Source><Stable Diabetes Mellitus><Stimulation of Cell Proliferation><Stroke><Stromal Cell-Derived Factor 1><T2 DM><T2D><T2DM><TLSF-A><TLSF-B><TPAR1><Testing><Tissue Growth><Transplacental Exposure><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States National Institutes of Health><Uterus><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Permeability Factor Receptor><Vascularization><adiposity><adult onset diabetes><adulthood><autophagy><biologic><biological signal transduction><brain attack><cardiovascular disorder><causation><cell motility><cerebral vascular accident><cerebrovascular accident><chemoattractant cytokine><chemokine><complications during pregnancy><corpulence><cytokine><death among neonates><death among newborns><death in neonates><death in newborn><disease causation><embryo attachment><excretion><fetal><hIRH><high blood pressure><high risk><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><impaired fetal growth><implantation><improved><in vivo Model><inhibitor><innovate><innovation><innovative><insight><insulin resistant><insulin tolerance><intra-uterine growth><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth><intrauterine growth restriction><ketosis resistant diabetes><maternal-fetal interface><maturity onset diabetes><migration><model of animal><mortality><mortality among neonates><mortality among newborns><mortality in neonates><mortality in newborns><natural Blastocyst Implantation><neonatal death><neonatal demise><neonatal morbidity><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><newborn death><newborn morbidity><newborn mortality><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><offspring><ontogeny><pathophysiology><placenta growth factor><placental abruption><potential biological marker><potential biomarker><pre-eclamptic><pregnancy toxemia/hypertension><pregnancy-related complications><prenatal growth disorder><product placenta growth factor><receptor><recruit><response><skills><social role><stillbirth><stillborn><stroked><strokes><stromal cell-derived factor-1alpha><success><trophoblast><type 2 DM><type II DM><type two diabetes><womb>