DAMP-RAGE Signaling and Fetal Injury in Inflammation-Induced Preterm Birth

炎症引起的早产中的 DAMP-RAGE 信号传导和胎儿损伤

• 批准号: 8727308
• 负责人: IRINA A BUHIMSCHI
• 金额: $ 25.88万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727308
• 关键词: Acetylcysteine; Acute; Advanced Glycosylation End Products; Animal Model; Animals; Antibodies; Antioxidants; Architecture; Biological Assay; Biological Markers; Birth; Blocking Antibodies; Brain; Calgranulin A; Cerebral Palsy; Cessation of life; Chronic; Endothelial Cells; Endotoxins; Experimental Models; Family; Fetus; Functional disorder; Genetic; Genetic Engineering; Gestational Age; Glutathione; HMGB1 Protein; Homeostasis; Human; Immune response; In Vitro; Incidence; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Laboratories; Lead; Ligands; Liver; Mammals; Mediator of activation protein; Membrane; Molecular; Molecular Target; Mus; NF-kappa B; Neonatal; Neonatal Mortality; Normal tissue morphology; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Pattern; Play; Pregnancy; Premature Birth; Premature Infant; Prematurity of fetus; Process; Protein Family; Proteins; Proteomics; Receptor Activation; Role; S100 Calcium Binding Protein; S100 Proteins; S100A12 gene; S100A8 gene; Severities; Signal Transduction; System; Systemic infection; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Tocolysis; Transgenic Organisms; Umbilical Cord Blood; adverse outcome; cell injury; efficacy testing; ethyl pyruvate; fetal; fetus cell; fighting; immunoglobulin receptor; improved; in utero; in vivo; inhibitor/antagonist; insight; intraamniotic infection; member; microbial; model design; mouse model; neonatal morbidity; neurotrophic protein S100beta; novel; oxidation; premature; prevent; prototype; public health relevance; receptor; response; restoration; therapy development; treatment strategy

PROJECT SUMMARY /ABSTRACT Strong correlations exist between intra-uterine and/or fetal inflammation, prematurity and incidence of adverse neonatal outcomes, including cerebral palsy. If targeted interventions to improve outcome are to be developed we need to fully understand the molecular mechanisms which inadvertently cause fetal cell damage and tissue injury. Damage-associated molecular pattern molecules (DAMPs) are a pleiotropic group of intra-cellular proteins including high-mobility group box 1 protein (HMGB1) and members of the S100 calcium binding protein family (i.e., S100 A12, S100A8, S100B). When released into the extra-cellular compartment as a result of inflammation or oxidative stress, DAMPs become "danger signals" by activating endogenous receptors such as the receptor of advanced glycation end-products (RAGE). Engagement of RAGE leads to cellular dysfunction and injury driven by oxidative stress and sustained activity of nuclear factor-kappa B (NF¿B). Using proteomics we discovered that S100A12 plays a key role in orchestrating the intra-amniotic inflammatory response to infection via RAGE activation. We have also shown that human fetuses with heightened inflammatory statuses have increased systemic levels of prototype DAMPs such as HMGB1 and S100B. In addition, in a mouse model of endotoxin induced fetal damage we demonstrated that maternal inflammation is associated with fetal oxidative stress and depletion of the intracellular antioxidant glutathione. In the same experimental model we further provided evidence that HMGB1 and RAGE and over-expressed in the liver and brain of the fetuses exposed to inflammation in utero. This body of knowledge, corroborated with the evidence that HMGB1 and S100 proteins are putative RAGE ligands, has led us to propose an active role for the DAMP- RAGE axis in inducing antenatal end-organ damage in the setting of intra-amniotic infection and prematurity. To test this hypothesis, three aims will be pursued: 1) Specific Aim 1 is geared to provide in vivo observational evidence that intra-uterine inflammation induces an imbalance in the redox homeostasis of the human fetus, causing release of DAMP proteins and antenatal fetal cellular damage via RAGE activation; 2) In Specific Aim 2 we will explore, in vitro, the mechanism and functional role of prototypical DAMPs and RAGE signaling in inducing cellular injury in a relevant bioassay. We will test the efficacy of anti-HMGB1 and anti-RAGE blocking antibodies or potential therapeutic agents such as N-acetylcysteine and ethyl pyruvate to reverse the damaging effects of the DAMP-RAGE axis activation; 3) In Specific Aim 3, by using unique genetically engineered RAGE deficient (RAGE-/-) and RAGE transgenic (RAGETg+) animals, we plan to provide insight into RAGE signaling as the common and obligatory pathway leading to fetal damage and explore the value of DAMP and RAGE antagonism as treatment strategies in vivo. By completing these aims we hope to provide novel insight into the processes leading to end-organ damage in premature infants and identify new classes of molecular targets that can modulate the inflammatory response of the fetus and improve outcomes.

项目总结/摘要 子宫内和/或胎儿炎症、早产和不良反应发生率之间存在强相关性。 新生儿结局，包括脑瘫。如果要制定有针对性的干预措施以改善结果， 我们需要充分了解无意中导致胎儿细胞和组织损伤的分子机制 损伤损伤相关分子模式分子（DAMPs）是一组多效性的细胞内 蛋白质包括高迁移率族蛋白1（HMGB 1）和S100钙结合蛋白 蛋白质家族（即，S100 A12、S100 A8、S100 B）。当被释放到细胞外时 在炎症或氧化应激中，DAMPs通过激活内源性受体成为“危险信号”， 作为晚期糖基化终产物（Advanced Glycation End-products，简称AGEs）的受体。细胞的参与导致细胞 由氧化应激和核因子-κ B（NF B）的持续活性驱动的功能障碍和损伤。使用 蛋白质组学研究发现，S100 A12在协调羊膜内炎症反应中起着关键作用， 对感染的反应。我们还发现， 炎症状态增加了原型DAMP如HMGB 1和S100 B的全身水平。在 此外，在内毒素诱导的胎儿损伤的小鼠模型中，我们证明母体炎症是 与胎儿氧化应激和细胞内抗氧化剂谷胱甘肽的消耗有关。在同一 实验模型进一步证明HMGB 1和HMGB 2在肝脏中过度表达， 在子宫内暴露于炎症的胎儿的大脑。这一知识体系，与证据相印证 HMGB 1和S100蛋白是假定的DAMP配体，这使我们提出DAMP的积极作用， 羊膜内感染和早产时胎盘轴诱导产前终末器官损伤 为了检验这一假设，将追求三个目标：1）具体目标1是为了提供体内观察 子宫内炎症诱导人胎儿氧化还原稳态失衡的证据， 引起DAMP蛋白质的释放和产前胎儿细胞损伤，通过β-内酰胺酶激活; 2）在特定的目标 2我们将在体外探索原型DAMPs和BMPs信号转导的机制和功能作用， 在相关生物测定中诱导细胞损伤。我们将测试抗HMGB 1和抗HMGB 2阻断的功效。 抗体或潜在的治疗剂如N-乙酰半胱氨酸和丙酮酸乙酯，以逆转 DAMP-β-淀粉样蛋白轴激活的破坏作用; 3）在特定目标3中，通过使用独特的遗传学方法， 工程化的RAGETg缺陷（RAGETg-/-）和RAGETg转基因（RAGETg+）动物，我们计划提供深入了解 探讨胎儿宫内窘迫信号转导作为导致胎儿损伤的共同和必然途径的价值， 作为体内治疗策略的DAMP和β受体拮抗剂。通过实现这些目标，我们希望提供 对导致早产儿终末器官损伤的过程的新见解，并确定新的类别， 可以调节胎儿炎症反应并改善结局的分子靶点。

项目成果

Calciprotein particles as potential etiologic agents of idiopathic preterm birth.

钙蛋白颗粒作为特发性早产的潜在病因。

• DOI: 10.1126/scitranslmed.aah4707
• 发表时间: 2016
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Shook,LydiaL;Buhimschi,CatalinS;Dulay,AntonetteT;McCarthy,MeganE;Hardy,JohnT;DuzyjBuniak,ChristinaM;Zhao,Guomao;Buhimschi,IrinaA
• 通讯作者: Buhimschi,IrinaA

Tenascin-X in amniotic fluid and reproductive tissues of pregnancies complicated by infection and preterm prelabor rupture of membranes†.

妊娠期羊水和生殖组织中的腱蛋白-X 并发感染和早产胎膜破裂。

• DOI: 10.1093/biolre/ioy216
• 发表时间: 2019
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Rood,KaraM;Buhimschi,CatalinS;Zhao,Guomao;Oliver,EmilyA;Summerfield,Taryn;Bahtiyar,MertOzan;Buhimschi,IrinaA
• 通讯作者: Buhimschi,IrinaA

Evidence for participation of neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9 (NGAL•MMP-9) complex in the inflammatory response to infection in pregnancies complicated by preterm birth.

• DOI: 10.1111/aji.12523
• 发表时间: 2016-08
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Rood KM;Buhimschi IA;Rodewald Millen K;Bahtiyar MO;Thung S;Summerfield T;Zhao G;Ackerman W 4th;Shellhaas C;Samuels P;Buhimschi CS
• 通讯作者: Buhimschi CS

Serum and Urine Thioflavin-T-Enhanced Fluorescence in Severe Preeclampsia.

• DOI: 10.1161/hypertensionaha.118.11034
• 发表时间: 2018-06
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Millen KR;Buhimschi CS;Zhao G;Rood KM;Tabbah S;Buhimschi IA
• 通讯作者: Buhimschi IA