Administrative Supplement to Intercellular interactions define cell migrations and transitions that maintain fetal membrane homeostasis

细胞间相互作用的行政补充定义了维持胎膜稳态的细胞迁移和转变

• 批准号: 10177264
• 负责人: Arum Han
• 金额: $ 28.09万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-12 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10177264
• 关键词: Address; Administrative Supplement; Animal Model; Anti-Inflammatory Agents; Automobile Driving; Blood Vessels; Cells; Cellular Stress; Cervical Ripening; Chorion; Clinical; Clinical Trials; Coculture Techniques; Data; Decidua; Decidua Basalis; Development; Devices; Disease; Drug Modelings; Effectiveness; Encapsulated; Endothelial Cells; Experimental Models; Fetal Membranes; Fetal Tissues; Fetus; Funding; Homeostasis; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune; In Situ; In Vitro; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Kinetics; Knowledge; Lead; Maternal Mortality; Maternal-Fetal Exchange; Membrane; Metabolism; Modeling; Mothers; Mus; NF-kappa B; Neonatal Mortality; Oxidative Stress; Pathologic; Pathology; Perfusion; Pharmaceutical Preparations; Placenta; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Tests; Premature Birth; Premature Labor; Property; Route; Severities; Structure; Sulforaphane; Syncytiotrophoblast; System; Technology; Testing; Tissues; Toxic effect; Umbilical vein; United States National Institutes of Health; Uterine Contraction; absorption; base; cell motility; cigarette smoke; cigarette smoking; comorbidity; cost; cytotoxicity; cytotrophoblast; decidua parietalis; design; drug development; drug efficacy; drug testing; experimental study; extracellular vesicles; fetal; human tissue; in vivo; inhibitor/antagonist; microchip; neonatal morbidity; nonhuman primate; organ on a chip; preclinical evaluation; preclinical trial; response; rosuvastatin; success; successful intervention; therapeutic candidate; therapy design; tool; trophoblast

ABSTRACT Approximately 10.5% of all pregnancies end in preterm around the world. Spontaneous preterm birth (PTB) and preterm birth due to preeclampsia (PE) contribute to both maternal and neonatal mortality and morbidity. Current interventions for both these conditions are unsuccessful, and PTB and PE drug development has been hindered by inability of drugs to cross the feto-maternal (F-M) barriers to treat both the mother and her fetus and lack of proper ways of testing drug absorption, metabolism and cytotoxicity. Pathologically, PTB and a large subset of PE have inflammation as a major mechanism driving preterm labor or contributing to placental vascular pathology, respectively. Statins, competitive inhibitors of HMG-CoA reductase, have been shown to reduce the expression of pro-inflammatory mediators. They have been successfully tested to reduce inflammation and oxidative stress in both PTB and PE in vitro and animal models. Before these drugs can advance to clinical trials, their efficacy and mechanism of action on the F-M and understanding their perfusion kinetics across the F-M barriers are needed. However, current drug testing models have many limitations: 1) the mouse F-M interface does not structurally mimic human, and chorionic trophoblast is obscure in the mouse; 2) non-human primates models are cost prohibitive; 3) placental perfusions studies are restricted to the placental-decidual interface, and thus drugs’ passage through the other interface is not tested, confounding data and disrupting clinical trials. Besides, there are two distinct F-M interfaces: 1) between placenta and decidua basalis and 2) between fetal membranes and decidua parietalis. Drugs and/or other metabolites must pass through the two interfaces which are structurally and functionally very different. Therefore, simultaneous testing of both F-M interfaces is necessary. To address these limitations, we will use F-M interface organ-on- chips (OOCs) using cells from human tissues that can closely mimic the structure and functions of both F-M interfaces. In this OOC model, we will test statins’ (rosuvastatin and pravastatin) properties and efficacy in reducing inflammation. Aim 1 will test properties of drugs in two independent OOC models (placenta-decidua and fetal membrane- decidua interfaces). Aim 2 will recreate an inflammatory model of interfaces and test drugs’ efficacy. Aim 3 will integrate the two interfaces into one OOC device and test statins’ properties and efficacies. OOC models generated can test the effect of candidate therapeutic molecules to more rapidly bring experimental drugs (modeled using statins here) to streamline preclinical evaluation and minimize costs of clinical trials.

摘要 全世界约有10.5%的妊娠以早产结束。自发性早产 和早产由于先兆子痫（PE）有助于产妇和新生儿的死亡率和发病率。 目前对这两种疾病的干预是不成功的，PTB和PE药物的开发已经被证明是不成功的。 由于药物不能跨越母胎屏障，无法同时治疗母亲和胎儿， 缺乏适当的药物吸收、代谢和细胞毒性测试方法。病理上，PTB和a 大部分PE以炎症作为驱动早产或导致胎盘炎的主要机制， 血管病理学。他汀类药物是HMG-CoA还原酶的竞争性抑制剂， 减少促炎介质的表达。他们已经成功地测试，以减少 在体外和动物模型中PTB和PE两者中炎症和氧化应激。在这些药物 推进临床试验，其对F-M的疗效和作用机制，并了解其灌注 需要跨越F-M势垒的动力学。然而，目前的药物测试模型有许多局限性：1） 小鼠F-M界面在结构上不模仿人类，绒毛膜滋养层在小鼠F-M界面中不明显。 小鼠; 2）非人灵长类动物模型成本过高; 3）胎盘灌注研究仅限于 胎盘-蜕膜界面，因此未检测药物通过另一界面，混淆 数据和扰乱临床试验。此外，胎盘与胎盘间存在两种不同的F-M界面： 底蜕膜; 2）胎膜与壁蜕膜之间。药物和/或其他代谢物必须 通过结构和功能非常不同的两个接口。因此，同步 需要对两个F-M接口进行测试。为了解决这些限制，我们将使用F-M接口器官上， 使用来自人体组织的细胞的芯片（OOC），可以密切模仿F-M的结构和功能， 接口。在该OOC模型中，我们将测试他汀类药物（瑞舒伐他汀和普伐他汀）的性质和疗效， 减少炎症。 目的1将在两个独立的OOC模型（胎盘-蜕膜和胎膜-胎盘）中测试药物的性质。 蜕膜界面）。 目标2将重建界面的炎症模型并测试药物的功效。 目标3将把两个接口集成到一个OOC设备中，并测试他汀类药物的特性和功效。 生成的OOC模型可以测试候选治疗分子的效果，以更快地产生 实验药物（此处使用他汀类药物建模），以简化临床前评估并最大限度地降低 临床试验