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.

抽象的 全世界大约 10.5% 的妊娠以早产结束。 先兆子痫 (PE) 导致的早产会导致孕产妇和新生儿死亡率和发病率。 目前针对这两种情况的干预措施均不成功，PTB 和 PE 药物的开发已被搁置。 由于药物无法跨越胎儿-母体 (F-M) 障碍来治疗母亲及其胎儿 缺乏测试药物吸收、代谢和细胞毒性的适当方法。 PE 的很大一部分将炎症作为导致早产或导致胎盘脱落的主要机制 他汀类药物（HMG-CoA 还原酶的竞争性抑制剂）已被证明可以分别治疗血管病理学。 减少促炎介质的表达已被成功测试为减少。 在这些药物可以之前，PTB 和 PE 的体外和动物模型中存在炎症和氧化应激。 推进临床试验，了解它们对 F-M 的功效和作用机制，并了解它们的灌注 需要跨越 F-M 屏障的动力学然而，当前的药物测试模型有许多局限性：1) 小鼠 F-M 界面在结构上并不模仿人类，并且绒毛膜滋养层在 小鼠；2) 非人类灵长类动物模型成本高昂；3) 胎盘灌注研究仅限于 胎盘-蜕膜界面，因此药物通过另一个界面的通道没有经过测试，混淆 此外，还有两个不同的 F-M 界面：1）胎盘和胎盘之间。 基底蜕膜和 2) 胎膜和壁蜕膜之间 药物和/或其他代谢物必须。 通过结构和功能上非常不同的两个接口，因此是同时进行的。 需要对两个 F-M 接口进行测试，以解决这些限制，我们将使用 F-M 接口器官。 使用人体组织细胞的芯片（OOC），可以密切模仿 F-M 的结构和功能 在这个 OOC 模型中，我们将测试他汀类药物（瑞舒伐他汀和普伐他汀）的特性和功效。 减少炎症。 目标 1 将在两个独立的 OOC 模型（胎盘-蜕膜和胎膜- 蜕膜界面）。 目标 2 将重建界面炎症模型并测试药物的功效。 Aim 3 将把这两个接口集成到一台 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，以更快地带来 实验（此处使用药物他汀类药物建模）以简化临床前评估并最大限度地降低成本 临床试验。