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Principal Investigator: Manu Banadakoppa
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $401,250
Funding agency: National Heart Lung and Blood Institute
Preeclampsia (PE) is a pregnancy-specific syndrome and several putative mechanisms have been implicated in
the pathogenesis of PE including complement (C) cascade activation. C activation byproducts in the circulation
are elevated with pregnancy in women and they are further elevated significantly in PE women. Placental
deposition of C activation byproducts is also significantly elevated in PE compared to normotensive women. The
semi-allogenic nature of fetus/placenta induces maternal C cascade activation. To understand the cause-and-
effect relation between C activation and pregnancy hypertension, it is essential to gain insight into the
mechanistic pathways that link placental C activation to pregnancy hypertension and fetal growth restriction with
the view of targeting these pathways for potential therapeutic discoveries. One possible mechanism is that C
activation may promote systemic antiangiogenic and proinflammatory milieu, maternal vascular dysfunction,
hypertension and renal pathological changes. Further, C activation may induce placental fibrin deposition due to
crosstalk with coagulation system, promoting fetal growth restriction. In this application we will determine the
mechanisms that link C activation to pregnancy hypertension and fetal growth restriction using a novel
complement activation-based mouse model. This transgenic mouse model allows us to downregulate Crry in
an inducible, conditional and placenta specific manner and study its effects on various maternal systems.
Specific aim 1. To assess if placenta specific C activation promotes systemic antiangiogenic
and proinflammatory milieu, hypertension, maternal vascular dysfunction, and renal pathology
through C3a-C3aR and/or C5a-C5aR, STAT3 and ERK pathways. Hypothesis: C activation during
pregnancy promotes increased systemic levels of antiangiogenic (sFLT1, sEng) and proinflammatory
molecules (TNF-α, IL-6 and IL-8), reduced relaxation and increased contractile responses (vascular
dysfunction) of maternal peripheral arteries, hypertension, defective uterine spiral artery (SA)
remodeling, and glomerular endotheliosis (renal pathology) through C3a-C3aR/C5a-C5aR, STAT3 and
ERK pathways. Further, inhibition of C activation using specific inhibitor CR2-Crry ameliorates these C
induced changes. Specific aim 2. To test the hypothesis that C activation induces placental fibrin
deposition through its crosstalk with coagulation system promoting fetal growth restriction.
Hypothesis: C activation promotes fetal growth restriction by reducing fetal blood supply due to
placental peri-villous fibrin deposition through the disruption of tissue factor (TF) and von Willebrand
factor (vWF) homeostasis. C activation directly through C5a-C5aR signaling and indirectly through
proinflammatory cytokines IL6, IL8 and TNF-α induces the upregulation of TF, plasminogen activator
inhibitor 1 and vWF by endothelial cells and downregulates the ADAMTS-13 in liver.
Terms: <(TNF)-α><3-10C><ADAMTS><AMCF-I><Ablation><Allogenic><Amniotic Fluid><Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Inhibitors><Angiostatic Agents><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Aqua Amnii><Arteries><Autoregulation><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor Gene><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor 2 Gene><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF-2 Gene><BSF2><BSF2 Gene><Beta-2 Gene Interferon><Biological><Blood Coagulation Factor I><Blood Coagulation Factor III><Blood Coagulation Factor One><Blood Factor One><C 5b-9><C3 a><C3AR><C3AR1><C3AR1 gene><C3a><C3d Receptors><C5 a><C5a><C5b-9><CD 21 Antigens><CD 46 antigen><CD142 Antigens><CD21><CD21 Antigens><CD46><CD46 Antigen><CR2><CR2 Receptors><CXCL8><Cachectin><Cell Communication and Signaling><Cell Protection><Cell Signaling><Cell membrane><Cells Placenta-Tissue><Cessation of life><Circulation><Clotting><Coagulation><Coagulation Factor I><Coagulation Factor III><Coagulation Factor One><Coagulation Process><Coagulin><Complement><Complement 3a><Complement 3d Receptors><Complement 5a><Complement Activation><Complement C3a><Complement C5a><Complement Complex C5b-9><Complement Factor H><Complement Membrane Attack Complex><Complement Proteins><Complement Receptor><Complement Receptors 2><Cytolytic Terminal Complement Complex><Cytoplasmic Membrane><Cytoprotection><Data><Death><Deposit><Deposition><Disease><Disorder><Dysfunction><EPH Gestosis><Embryo><Embryonic><Endothelial Cells><Epidemiology><Epstein-Barr Virus Receptors><Factor H><Factor I><Factor III><Factor One><Fetal Growth Restriction><Fetal Growth Retardation><Fetal Reduction><Fetus><Fibrin><Fibrinogen><Functional disorder><Future><GCP1><Genes><Genetic Polymorphism><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Gestation><Gestational Hypertension><Glomerular Procoagulant Activity><HPGF><HSF Gene><Hepatocyte Stimulatory Factor Gene><Hepatocyte-Stimulating Factor><High Prevalence><Homeostasis><Human><Hybridoma Growth Factor><Hybridoma Growth Factor Gene><Hypertension><Hypertension induced by pregnancy><Hypertension-Associated Pregnancy Disorder><IFN-beta 2><IFNB2><IFNB2 Gene><IL-6><IL-6 Gene><IL-8><IL6><IL6 Protein><IL6 gene><IL8><IL8 gene><IUGR><Inflammatory><Inherited Predisposition><Inherited Susceptibility><Injury><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-6><Interleukin-6 Gene><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Investigation><K60><Kidney><Kidney Urinary System><Link><Liquid substance><Liquor Amnii><Liver><MCP antigen><MGI-2><Macrophage-Derived TNF><Mannan-Binding Lectin><Mannan-Binding Protein><Mannose Binding Lectin><Mannose-Binding Protein><Mannose-Specific Lectin><Maternal Mortality><Maternal-Fetal Exchange><Mediating><Medical><Membrane Attack Complex><Methodology><Mice><Mice Mammals><Miscarriage><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Multifetal Pregnancy Reduction><Murine><Mus><Myeloid Differentiation-Inducing Protein><Nature><Neovascularization Inhibitors><Normal Placentoma><PAI-1><PAI1><PLANH1><Pathogenesis><Pathologic><Pathology><Pathway interactions><Peripheral><Phase><Physiological Homeostasis><Physiopathology><Placenta><Placenta Embryonic Tissue><Placentome><Plasma Membrane><Plasmacytoma Growth Factor><Plasminogen Activator Inhibitor 1><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Associated Hypertension><Pregnancy Toxemias><Process><Proteins><Proteinuria-Edema-Hypertension Gestosis><Prothrombinase><Recombinant C5a><Regulation><Relaxation><Reporting><Ristocetin Cofactor><Ristocetin-Willebrand Factor><Rodent><Rodentia><Rodents Mammals><Role><SCYB8><STAT3><STAT3 gene><Selective Fetal Terminations><Serine or Cysteine Proteinase Inhibitor Clade E Member 1><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Spiral Artery><Spiral Artery of the Endometrium><Spontaneous abortion><Syndrome><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Terminal Complement Complex><Testing><Therapeutic><Thromboplastin><Tissue Factor><Tissue Factor Procoagulant><Tissue Thromboplastin><Transgenic Mice><Transplacental Exposure><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Type 1 Plasminogen Activator Inhibitor><Up-Regulation><Upregulation><Urothromboplastin><Uterus><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular blood supply><Villous><Woman><Women's mortality><Y protein><activation product><antiangiogenic><b-ENAP><biologic><biological signal transduction><blood supply><blood vessel disorder><complement pathway regulation><complementation><cytokine><cytoprotective><death among females><death among women><death in females><death in women><death rate among women><death rate in women><epidemiologic><epidemiological><female death><female mortality><fetal><fluid><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><hepatic body system><hepatic organ system><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disease of pregnancy><hypertensive disorder><impaired fetal growth><inflammatory environment><inflammatory milieu><inhibitor><injuries><insight><interferon beta 2><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><liquid><maternal death><maternal-fetal interface><membrane cofactor protein><mortality among females><mortality among women><mortality in females><mortality in women><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><normotensive><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><pathophysiology of pre-eclampsia><pathophysiology of preeclampsia><pathway><plasmalemma><polymorphism><pre-eclamptic><pregnancy hypertension><pregnancy toxemia/hypertension><prenatal growth disorder><renal><response><single nucleotide variant><social role><vascular dysfunction><vascular supply><vasculopathy><von Willebrand Factor><von Willebrand Protein><womb><women's death><women's death rate>