MetabolGut: a rapid assay platform to evaluate the impact drugs on lipid-handlingpathways and chylomicron-associated drug distribution using stem cell-drivenhuman absorptive enterocytes.

MetabolGut：一个快速检测平台，使用干细胞驱动的人体吸收性肠上皮细胞来评估药物对脂质处理途径和乳糜微粒相关药物分布的影响。

• 批准号: 10766493
• 负责人: Bill Thelin
• 金额: $ 34.33万
• 依托单位: ALTIS BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10766493
• 关键词: 3-Dimensional; Address; Amino Acids; Apical; Applications Grants; Architecture; Biological Assay; Biological Availability; Biosensor; Biotechnology; Blood Circulation; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cells; Chimeric Proteins; Chylomicrons; Collaborations; Colon; Detection; Dietary Fats; Disease; Donor person; Drug Kinetics; Drug Modelings; Drug Screening; Drug Transport; Elements; Enterocytes; Epidemic; Epithelium; Etiology; Excretory function; Exposure to; Fatty Acids; Fatty acid glycerol esters; Flow Cytometry; Foundations; Gene Transfer Techniques; Goals; Health; Hepatic; Human; Hydrogels; Hyperlipidemia; Hypertension; Insulin Resistance; Intestines; Kinetics; Lipids; Lipoproteins; Liver Circulation; Lymphatic System; Metabolic; Metabolic Diseases; Metabolism; Methods; Modality; Modeling; Nonesterified Fatty Acids; North Carolina; Nutrient; Obesity; Occupations; Oral; Organ Donor; Organ Transplantation; Organoids; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological; Physiology; Play; Pre-Clinical Model; Process; Proliferating; Property; Rapid screening; Reader; Reproducibility; Role; Scientist; Small Intestines; System; Technology; Thick; Thin Layer Chromatography; Tissues; Toxicology; Unhealthy Diet; Universities; Validation; Xenobiotics; absorption; cancer cell; cell type; commercialization; detection assay; detection limit; dietary; drug development; drug discovery; drug distribution; drug testing; high throughput screening; improved; in vitro Model; in vivo; innovation; lipophilicity; lymphatic circulation; metabolic engineering; metabolomics; monolayer; novel; novel strategies; nutrient absorption; preclinical efficacy; prototype; rapid detection; rapid test; sedentary; stem cells; sugar

Project Summary Maintaining healthy physiology of the human gut is a large focus of Pharma. Models to study drug/nutrient absorption, xenobiotics, toxicology, and preclinical efficacies are hampered by the lack of accurate, reproducible, and easy to use cell culture models to evaluate such topics. For these reasons, there is a strong need for better in vitro models that recapitulate disease states of the human gut, and better platforms for drug discovery and validation. Lipid-handling is central to human health conditions and pharmacokinetics. Lipid-related metabolic disorders (i.e. obesity, insulin resistance, hyperlipidemia, and hypertension) are a global epidemic and predicted to increase as sedentary jobs and unhealthy diets increase. Treatments for metabolic disorders are sparse with limited efficacy highlighting the need for more broadly effective drugs. Lipid-handling mechanisms by Absorptive Enterocytes (AEs) can strongly influence oral drug Absorption, Distribution, Metabolism and Excretion (ADME), and drug bioavailability can be negatively and positively regulated by AE lipid-handing as many lipid soluble drugs are associated with chylomicrons (CMs). CM-associated-drug export by AEs is a first-line metric of bioavailability for lipophilic drugs with no accurate preclinical model. New tactics that harness lipid- handling mechanisms have strong potential to improve drug engineering for metabolic diseases, bioavailability and efficacy. To meet this need Altis Biosystems Inc., an early-stage biotechnology company, will collaborate with scientists at the University of North Carolina at Chapel Hill to develop Absorptive Enterocytes (AEs) on a high-throughput 96-Traswell format. ‘MetabolGut’ is a monolayer of differentiated AEs derived from the foundational technology, RepliGutTM, which is a stem cell-driven monolayer of human epithelium derived the small intestine or colon of organ donors and contains all of the proliferative and differentiated cell types found in vivo. The goal of this Phase I proposal is to develop four innovative elements: 1) rapid fluorescent readouts for lipid absorption and export, 2) simultaneous rapid detection of barrier integrity and fatty acid export, 3) rapid and highly sensitive identification of fatty acid metabolic species using non-radioisotope methods, 4) rapid fluorescent quantification of chylomicron (CM) export. While elements 1-3 have shown substantial utility for academic studies, they will be explored for commercial viability. Element 4 will be developed de novo as it represents a new assay for high-throughput detection of CM export and CM-associated drug quantification.

项目摘要 维持人类肠道健康的生理学是药物的重点。研究模型 缺乏药物/营养滥用，异生元，毒理学和临床前效率受到阻碍 准确，可重现且易于使用细胞培养模型来评估此类主题。由于这些原因， 强烈需要更好地体外模型来概括人类肠道的疾病状态，并 更好的药物发现和验证平台。脂质处理是人类健康的核心 条件和药代动力学。与脂质相关的代谢性疾病（即肥胖，胰岛素抵抗， 高脂血症和高血压）是一种全球流行病，预计将增加为久坐的工作， 不健康的饮食增加。代谢性疾病的治疗稀疏，效率有限 需要更广泛有效的药物。吸收性肠细胞（AES）的脂质处理机制 可以强烈影响口服药物吸收，分布，代谢和排泄（ADME）和药物 生物利用度可以通过AE脂质手工进行负面调节，而多脂质可溶性 药物与乳糜微粒（CMS）有关。 AES由CM相关的药物出口是一线度量 没有准确的临床前模型的亲脂性药物的生物利用度。利用脂质的新战术 - 处理机制具有改善代谢疾病的药物工程的强大潜力， 生物利用度和效率。为了满足这一需求Altis Biosystems Inc.，早期生物技术 公司将与北卡罗来纳大学教堂山分校的科学家合作开发 高通量96-Traswell格式的吸收性肠细胞（AE）。 “代谢”是 从基础技术repliguttm衍生的AE分化的AE，这是干细胞驱动的 人类上皮的单层衍生出器官捐献者的小肠或结肠，并包含所有 在体内发现的增生剂和分化细胞类型。我提出的这个阶段的目标是 开发四个创新元素：1）脂质抽象和出口的快速荧光读数，2） 简单的快速检测屏障完整性和脂肪酸导出，3）快速且高度敏感 使用非放射性异位素方法鉴定脂肪酸代谢物种，4）快速荧光 乳糜微粒（CM）出口的量。元素1-3显示了实用性的 学术研究，将探索它们的商业生存能力。元素4从头开发为 它代表了CM出口和CM相关药物的高通量检测的新测定 数量。