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: 10491072
• 负责人: MISTY L GOOD
• 金额: $ 59.01万
• 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/10491072
• 关键词: 3-Dimensional; Address; Affect; Automobile Driving; Bacterial Translocation; Biological Models; Biopsy; Cause of Death; Cell Death; Cells; Childhood; Clinical; Coculture Techniques; Data; Development; Disease; Dose; Drug Screening; Endothelial Cells; Endothelium; Environment; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Excision; Failure; Functional disorder; Gastrointestinal Diseases; Genetic Transcription; Genome; Goals; Human; Hypermethylation; Immune; Immune response; Impairment; In Vitro; Infant; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Intestinal Diseases; Intestines; Knowledge; Lead; Libraries; Metadata; Methods; Methylation; Microfluidic Microchips; Modeling; Morbidity - disease rate; Mucous body substance; Necrotizing Enterocolitis; Neonatal; Operative Surgical Procedures; Organoids; Pathogenesis; Pathogenicity; Patients; Peristalsis; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Preclinical Testing; Premature Infant; Premature Infant Diseases; Process; Production; Research; Role; Safety; Scientist; Specimen; Stretching; Supportive care; Surgeon; System; Testing; Therapeutic; Tight Junctions; Toxic effect; Villus; antimicrobial; biobank; bisulfite sequencing; cell injury; cost; cost effective; cytokine; design; drug discovery; drug testing; dysbiosis; efficacy evaluation; epigenomics; genome-wide; high risk infant; human disease; in vitro Model; innovation; insight; intestinal epithelium; microbial; microbiome; microbiome components; microbiota; microphysiology system; mortality; multidisciplinary; multiple omics; novel; novel therapeutic intervention; novel therapeutics; patient population; pre-clinical; precision medicine; premature; prevent; proteomic signature; regenerative; screening; therapeutic candidate; therapeutic evaluation; tool; transcriptomics

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.

项目摘要/摘要 该提案的目的是研究人类的微生物生理肠道片平台的作用 精密医学工具，建模毁灭性疾病，影响过早的婴儿 小肠结肠炎（NEC）。我们使用类型器和“芯片NEC”模型开发了NEC的临床前模型 在体外概括人类疾病的肠道环境的系统，获得了对疾病的新见解 发病机理和测试我们模型的功能和临床实用性，以评估候选人的有效性 疗法。我们的NEC-on-A-Chip模型利用了早产婴儿肠道器官的组合 人体内皮细胞和患者衍生的微生物群，以重现过早肠道的关键方面 病理生理学。我们的初步研究表明，这些成分在肠道上的共同培养 芯片微流体设备产生在人NEC中看到的临床特征，例如肠道屏障衰竭 细胞紧密连接的崩溃，上皮细胞增殖减少，促进 炎性细胞因子反应以及大量细胞死亡。在此提案中，我们将使用几个 多摩变的方法来表征我们的NEC-on-A-CHIP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的NEC生物座席，由详细的临床元数据组成 对应于过多的人类标本，包括从活检中培养的肠道器官 有或没有NEC的早产婴儿。此外，我们创建了高通量和高含量药物 使用过早的肠癌筛选平台鉴定抑制药物或化合物 在体外看到的致病性炎症反应。此外，我们将展示功能和临床实用程序 我们的患者衍生的NEC-on-A-Chip模型是测试剂量，效率和 候选治疗的毒性。为了成功完成这些研究，我们建立了一个多学科的研究 团队与新生儿学家，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。综上所述，这些研究将在我们的理解中取得重大概念上的进步 与发育过早的肠的微生物组的多细胞相互作用，并提供了新的模型 系统和临床前平台，通过这些平台鉴定和测试NEC和其他的治疗 可以在这个脆弱的患者人群中进行肠道疾病。