NETs as therapeutic targets in obstetric APS

NETs 作为产科 APS 的治疗靶点

基本信息

批准号：
10786977
负责人：
Jason Knight
金额：
$ 42.9万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-26 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10786977
关键词：
ADORA2A gene Adjuvant Therapy Affinity Agonist Antiphospholipid Antibodies Antiphospholipid Syndrome Aspirin Attenuated Autoimmune Diseases Blood Vessels Chromatin Clinic Clinical Trials Colchicine Complement Complement Activation Data Deposition Dipyridamole Discipline of obstetrics Dose Evaluation Event Familial Mediterranean Fever Fetal Death Fetal Growth Retardation Functional disorder Ginger Heparin Histopathology Homeostasis Human Hydroxychloroquine Hyperactivity Hypertension Immunoglobulin G Immunologic Factors Individual Internet Invaded Knockout Mice Leukocyte Elastase Leukocytes Ligands Mediating Modeling Monitor Morbidity - disease rate Mus Natural Supplement Neurofibrillary Tangles Neutrophil Infiltration Pathogenicity Patient Care Patients Pharmaceutical Preparations Placenta Placental Insufficiency Pre-Eclampsia Pregnancy Pregnancy loss Premature Birth Property Prospective Studies Protein-arginine deiminase Proteins Proteinuria Purinergic P1 Receptors Rewards Risk Role Safety Secondary to Selectins Signal Transduction Spiders Standardization Thrombosis Tissues Venous Villous beta 2-glycoprotein I extracellular fetal fetal loss improved outcome inhibitor microbicide migration neutrophil new therapeutic target novel novel therapeutics obstetric outcomes pharmacologic pre-clinical pregnant prevent restraint stillbirth targeted treatment therapeutic target thrombotic trophoblast

项目摘要

PROJECT SUMMARY/ABSTRACT Pregnant individuals with the autoimmune disease known as antiphospholipid syndrome (APS) have a markedly increased risk of late-term stillbirth, intrauterine growth restriction, and severe preeclampsia. Despite some progress as to how we treat obstetric APS in our clinics—including the routine administration of aspirin and heparins—prospective studies have found that roughly 1 in 8 APS pregnancies will still end with fetal demise. Thrombosis is actually a rare feature of APS placental histopathology; instead, common abnormalities include deposition of complement split products, exuberant decidual neutrophil recruitment, and inadequate tissue remodeling by extravillous trophoblasts. Indeed, our group previously detected neutrophil extracellular traps (NETs) in the intervillous space of human APS placentae, where they may disrupt normal trophoblast functions. NETs are spider web-like tangles of chromatin and microbicidal proteins expelled from activated neutrophils via “NETosis.” We have previously found that antiphospholipid antibody (aPL)-mediated NETosis is required for thrombosis in models of APS—and have identified some pharmacologic strategies that can help restore neutrophil homeostasis (including colchicine, adenosine receptor agonists, selectin ligand inhibitors, and even natural supplements such as ginger). Would such approaches prove valuable if extended to APS-associated obstetric morbidity? We believe there is an urgent need to answer this question. Bolstered by new data indicating that NETosis blockade protects APS mice from fetal loss, the hypothesis shepherding this proposal is that NETosis inhibitors such as colchicine or dipyridamole could find a place in our clinics as adjuvants therapies. While this study's disruptive hypothesis means it is not without risk, the reward will hopefully be sufficient preclinical data to support a clinical trial of a drug like colchicine—which is already known to have a good safety profile in pregnancy based on its routine use in Familial Mediterranean Fever. Aim 1 will elucidate mechanisms by which NETosis may contribute to aPL-mediated obstetric morbidity. Successful completion of this Aim will identify (i) the obstetric APS patient-derived aPL most likely to trigger NETosis, (ii) the role of NETs in amplifying aPL-mediated trophoblast dysfunction, and (iii) whether blocking NETosis reduces aPL-mediated obstetric morbidity in mice. Aim 2 will determine the extent to which administering colchicine and/or adenosine receptor agonists mitigates aPL-mediated obstetric morbidity in mice. Successful completion of this translational Aim is expected to further elucidate the role of NETs in aPL-mediated obstetric morbidity, while potentially identifying new therapies that merit urgent evaluation in the clinic.