Neonatal gut-on-a-chip platform for high content drug testing and precision medicine

用于高内涵药物测试和精准医学的新生儿肠道芯片平台

• 批准号: 10594705
• 负责人: MISTY L GOOD
• 金额: $ 53.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594705
• 关键词: Neonatal; gut; chip; platform; content

Project Summary/Abstract The goal of this proposal is to investigate the role of a human microphysiologic intestine-on-a-chip platform as a precision medicine tool to model a devastating disease affecting premature infants known as necrotizing enterocolitis (NEC). We developed preclinical models of NEC using both organoids and a “NEC-on-a-chip” model system to recapitulate the intestinal environment of the human disease in vitro, gain new insights into disease pathogenesis and test the functional and clinical utility of our models to evaluate the efficacy of candidate therapeutics. Our NEC-on-a-chip model utilizes a combination of premature infant intestinal organoids along with human endothelial cells and patient-derived microbiota, to recreate critical aspects of premature gut pathophysiology. Our preliminary studies demonstrate that co-culture of these components on intestine-on-a- chip microfluidic devices produces clinical features seen in human NEC such as gut barrier failure with the breakdown of cellular tight junctions, decreased epithelial cell proliferation, a dramatic increase in the pro- inflammatory cytokine response, as well as a significant amount of cell death. In this proposal, we will use several multi-omic approaches to characterize our NEC-on-a-chip model and compare to the human NEC phenotype. To achieve this, we developed a multi-center NEC Biorepository, which consists of detailed clinical metadata corresponding to a plethora of human specimens, including intestinal organoids cultured from the biopsies of premature infants with or without NEC. Furthermore, we have created a high-throughput and high-content drug screening platform using premature intestinal organoids to identify drugs or compounds that inhibit the pathogenic inflammatory responses seen in vitro. Moreover, we will demonstrate the functional and clinical utility of our patient-derived NEC-on-a-chip model as a precision medicine platform to test the dosing, efficacy, and toxicity of candidate therapeutics. To successfully complete these studies, we established a multi-disciplinary team with the expertise of a Neonatologist, Cell Biologist, Pediatric Surgeon, Genome Scientist and Bioinformatician. Taken together, these studies will make a significant conceptual advance in our understanding of the multicellular interactions with the microbiome of the developing premature intestine and provide new model systems and preclinical platforms by which the identification and testing of therapeutics for NEC and other intestinal diseases can be performed in this vulnerable patient population.

项目概要/摘要 该提案的目标是研究人体微生理肠道芯片平台作为 精准医学工具可以模拟一种影响早产儿的毁灭性疾病，即坏死性疾病 小肠结肠炎（NEC）。我们使用类器官和“NEC 芯片”模型开发了 NEC 临床前模型 系统在体外重现人类疾病的肠道环境，获得对疾病的新见解 发病机制并测试我们模型的功能和临床效用，以评估候选药物的功效 疗法。我们的 NEC 芯片模型结合了早产儿肠道类器官和 人内皮细胞和患者来源的微生物群，以重建早产肠道的关键方面 病理生理学。我们的初步研究表明，这些成分在肠上的共培养 芯片微流控装置产生人类 NEC 中常见的临床特征，例如肠道屏障衰竭 细胞紧密连接的破坏，上皮细胞增殖减少，亲细胞数量急剧增加 炎症细胞因子反应，以及大量细胞死亡。在这个提案中，我们将使用几个 多组学方法来表征我们的 NEC 芯片模型并与人类 NEC 表型进行比较。 为了实现这一目标，我们开发了一个多中心 NEC Biorepository，其中包含详细的临床元数据 对应于大量的人类样本，包括从活组织检查中培养的肠道类器官 有或没有 NEC 的早产儿。此外，我们还创造了一种高通量、高含量的药物 使用早产儿肠道类器官的筛选平台来识别抑制肠道类器官的药物或化合物 体外观察到的致病性炎症反应。此外，我们将展示功能和临床实用性 我们将源自患者的 NEC 芯片模型作为精准医疗平台来测试剂量、功效和 候选疗法的毒性。为了成功完成这些研究，我们建立了一个多学科的 团队由新生儿学家、细胞生物学家、儿科外科医生、基因组科学家和 生物信息学家。总而言之，这些研究将在我们的理解上取得重大的概念性进展 多细胞与发育中的早产儿肠道微生物组的相互作用，并提供新模型 系统和临床前平台，用于 NEC 和其他疗法的鉴定和测试 肠道疾病可以在这个脆弱的患者群体中进行。