A Mucus-producing Intestinal Epithelium Model for In Vitro Drug Absorption Testing

项目摘要 粘液层是防止微生物、消化酶渗透的第一道防线。 以及酸、消化的食物颗粒、微生物副产品和与食物相关的毒素。这一层覆盖了内部 胃肠道表面，润滑管腔内容物，并作为细菌和其他抗原物的物理屏障 管腔中存在的物质。靠近胃肠道上皮屏障的潮湿、营养丰富的粘液层 肠道在维持肠道内环境稳定方面也是必不可少的，并包含一个蓬勃发展的生物膜，包括 有益的和致病的微生物种群。然而，事实证明，粘液很难研究，因为它 成分和功能的复杂性，以及基本上缺乏高质量的纯化样本或细胞- 含有粘液的基本培养系统。 该项目将建立一个胃肠道(GI)模型，用于收集生理上相关的粘液 以及一种拥有天然粘液层的上皮培养系统。在阿尔蒂斯发电能力的基础上 具有更大生理相关性的模型使用供体来源的细胞，该计划将建立关键协议 和工作流程，以确保可靠和可重复的粘液层，以在体内额外复制GI形态 和功能。在目标1中，我们将最终确定两种小鼠上皮细胞产生粘液的体外方案 和大肠(空肠和横结肠)，它们的生产功能截然不同 粘液。这些数据将建立关键的质量指标，使Altis能够与我们的行业和 不同方面的学术客户早期药物开发和炎症性发展 疾病和微生物组研究。根据之前与我们的药物开发客户的讨论， 我们认为这种模式的商业潜力很大，特别是考虑到阿尔蒂斯目前的独特能力 站台。

Project Summary The mucus layer is the first line of defense against infiltration of microorganisms, digestive enzymes and acids, digested food particles, microbial by-products, and food-associated toxins. This layer coats the interior surface of the GI tract, lubricates luminal contents and acts as a physical barrier to bacteria and other antigenic substances present in the lumen. The moist, nutrient-rich mucus layer adjacent to the epithelial barrier of the GI tract is also essential in the maintenance of intestinal homeostasis and contains a thriving biofilm including beneficial and pathogenic microbial populations. However, mucus has proven difficult to study, owing to it compositional and functional complexity and a substantial lack of either high-quality purified samples or cell- based culture systems containing mucus. This project will establish a gastrointestinal (GI) model for both harvesting physiologically relevant mucus and an epithelial culture system that possess a native mucus layer. Building on Altis’ capabilities to generate models with greater physiological relevance using donor-derived cells, this program will establish key protocols and workflows to ensure a reliable and reproducible mucus layer to additionally replicate in vivo GI morphology and function. In Aim 1, we will finalize in vitro protocols for mucus production in epithelia from both the small and large intestine (jejunum and transverse colon), which are well-described to production functionally distinct mucus. These data will establish key quality metrics enabling Altis to explore R&D studies with our industry and academic clients in diverse aspects of early stage of drug development and the development of inflammatory disease and microbiome research. Based on prior discussions with our pharmaceutical development customers, we view the commercial potential for this model as strong, especially given the unique capabilities of Altis’ current platform.