Developing trimester-specific placenta organ-on-chips to model healthy and oxidative stress and inflammation-associated pathologies

开发妊娠期特异性胎盘器官芯片来模拟健康和氧化应激以及炎症相关的病理学

• 批准号: 10732666
• 负责人: Lauren Stafford Richardson
• 金额: $ 55.24万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732666
• 关键词: 37 weeks gestation; Adverse event; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Biochemistry; Blood; Blood capillaries; Cell model; Cell physiology; Cells; Cellularity; Circulation; Clinical Trials; Complex; Cysteine; Decidua; Decidua Basalis; Development; Developmental Delay Disorders; Disease; Disease model; Endothelium; Engineering; Environment; Environmental Impact; Exhibits; Fetal Growth Retardation; Fetal Membranes; Functional disorder; Gestational Age; Gestational Diabetes; Growth; Homeostasis; Human; Hydrogen Peroxide; Image; Immune; Immunobiology; Infection; Inflammation; Interleukin-10; Knowledge; Lead; Low Birth Weight Infant; Maternal Mortality; Maternal-Fetal Exchange; Measures; Mediating; Modeling; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Neonatal Mortality; Oxidative Stress; Oxidative Stress Induction; Oxygen; Pathology; Perfusion; Pharmaceutical Preparations; Physiological; Physiology; Pilot Projects; Placenta; Placenta Diseases; Placental Biology; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Trimesters; Premature Birth; Proteomics; Research; Risk; Risk Reduction; Role; Safety; Sampling; Scientist; Stromal Cells; Structure; Syncytiotrophoblast; TNF gene; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Villus; adverse pregnancy outcome; age related; body system; cell growth; cell injury; cell type; cigarette smoke; cost; design; disability; efficacy testing; exosome; experience; experimental study; fetal; in utero; in vitro Model; in vivo; innovation; mortality; nonhuman primate; novel; organ on a chip; placental transfer; preclinical trial; pregnant; prevent; successful intervention; tissue/cell culture; trophoblast

ABSTRACT Placental dysfunctions arising from oxidative stress (OS) and inflammation are major pathophysiological contributors to adverse pregnancy outcomes (APOs; ~11% of all pregnancies). Risk-induced OS and inflammation compromise various placental homeostatic functions, leading to APOs. The majority of APOs lead to either indicated or spontaneous preterm birth, as delivery is the only option to reduce the risk of feto- maternal mortalities and morbidities. Currently, no successful interventions are available for reducing the risk of APOs. The lack of therapeutic strategies preventing APOs is partly due to the lack of models that accurately recreate human placenta pathology and the in utero environment of the human fetal (placental)-maternal (F-M) barriers. The placenta exhibits distinct cellularity in each of the pregnancy trimesters, which are under different O2 environments. Current models (e.g., explant, 2D and transwell cultures, placental perfusion, and animals) have several limitations as they do not address the complex and dynamic interplay between placental and maternal cells, which has hindered understanding of placental physiology during normal pregnancies and pathologies in APOs. To overcome these current limitations, we will develop a novel Placental (fetal)-decidual (Maternal) interface (PMi) 5-chamber organ-on-chip (PMi-OOC) designed to mimic PMi structure and function representing each of the three pregnancy trimesters, with specific O2 environments. New knowledge gained from this study will be crucial in elucidating placental biology/pathology. Using three aims, we advance our current placenta OOC and test the hypothesis that OS and inflammation-associated placental pathologies compromise PMi homeostasis, leading to APOs. Specific Aims are: SA 1: Engineer all three trimester-specific “healthy, physiological state” PMi-OOCs with or without the addition of maternal decidua immune cells. SA2: Develop a trimester-specific disease state model to study the effects of OS and inflammation. This model will be validated with the use of antioxidant N-Acetyl-L-Cysteine or anti-inflammatory interleukin-10 to mitigate the effect of OS or inflammation. This research will develop trimester-specific placenta OOC models that can be utilized to study healthy, and disease states of pregnancy as well as conduct various preclinical trials.

抽象的 氧化应激（OS）和炎症引起的胎盘功能障碍是主要的病理生理学 不良怀孕结果的贡献者（Apos；所有怀孕的11％）。风险引起的操作系统和 炎症会损害各种位置稳态功能，从而导致APO。大多数apos 导致指示或赞助早产，因为交付是降低胎儿风险的唯一选择 孕产妇的死亡率和病态。目前，没有成功的干预措施可降低 apos。缺乏预防APO的治疗策略的部分原因是缺乏准确的模型 重现人类胎儿（胎盘） - 男性（F-M）的子宫内环境 障碍。 lopeta在每个怀孕三物种中都表现出明显的细胞性，它们处于不同的状态 O2环境。当前模型（例如，外植体，2D和Transwell培养物，胎盘灌注和动物） 有几个限制，因为它们无法解决胎盘和 母体细胞，这阻碍了正常怀孕期间的斑点生理学的了解 APO中的病理。为了克服这些当前的局限性，我们将发展一个新颖的胎盘（胎儿） （母体）界面（PMI）5腔器官片（PMI-OOC），旨在模仿PMI结构和功能 代表三个怀孕三体，具有特定的O2环境。获得了新知识 从这项研究中，对于阐明位置生物学/病理学至关重要。使用三个目标，我们提高了我们的 当前的胎盘OOC并检验了OS和感染相关的置换病理的假设 妥协PMI稳态，导致Apos。 具体目的是： SA 1：工程师所有三个孕妇特定的“健康，身体状态” PM-OOC，有或没有 添加母体Decidua免疫球。 SA2：开发孕妇特异性疾病状态模型来研究OS和炎症的影响。这 模型将通过使用抗氧化剂N-乙酰L-半胱氨酸或抗炎白介素100验证 减轻OS或炎症的影响。 这项研究将开发可用于研究健康的三个月特异性pleceta ooc模型，并且 疾病的怀孕状态以及进行各种临床前试验。