Development of Human Intestinal Simulacra

人体肠道模拟物的开发

• 批准号: 8948275
• 负责人: Nancy L. Allbritton
• 金额: $ 90.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8948275
• 关键词: Achievement; Adherent Culture; Architecture; Autistic Disorder; Bacteria; Behavior; Biological Assay; Biological Models; Biology; Biopsy; Butyrates; Caliber; Cardiovascular Diseases; Cell Culture System; Cell Differentiation process; Cell physiology; Cells; Chemicals; Coculture Techniques; Colon; Communities; Controlled Environment; Development; Devices; Diabetes Mellitus; Diet; Dietary Factors; Digestive System Disorders; Dimensions; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; Food; Gases; Genetic Predisposition to Disease; Geometry; Germ-Free; Gnotobiotic; Goals; Growth; Growth Factor; Growth and Development function; Health; Human; Human Development; Hydrogels; Immune Tolerance; In Vitro; Individual; Interdisciplinary Study; Intestinal Diseases; Intestinal Mucosa; Intestines; Investigation; Length; Life; Link; Mediating; Medicine; Metabolic; Metagenomics; Methyl Green; Microbe; Microfabrication; Mitogens; Molecular Conformation; Mucous Membrane; Mus; Organ; Organism; Organoids; Oxygen; Patients; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Porosity; Positioning Attribute; Process; Protocols documentation; Research Personnel; Research Project Grants; Role; Stem cells; Structure; Surface; System; Technology; Testing; Tissues; Tube; Work; advanced system; base; bone morphogenic protein; community living; genome wide association study; gut microbiota; human disease; human stem cells; human tissue; innovation; insight; intestinal epithelium; meetings; metabolomics; microbiome; monolayer; morphogens; mouse model; new technology; novel; prevent; public health relevance; scaffold; self-renewal; stem; stem cell niche; three dimensional structure; tool

 DESCRIPTION (provided by applicant): In the current application, a collaborative, multidisciplinary research project is proposed that has the potential to create a new paradigm for the study of human physiology in health and disease. A state-of-the-art microfabricated platform will be developed to create a functional, in vitro replica, i.e. simulacrum, of the human colonic epithelium and its associated microbiome. This new technology will be used to perform novel studies and hypothesis testing of intestinal physiology that cannot currently be performed. Furthermore, the technology and protocols developed here will establish the basis for creating organ simulacra from normal and diseased primary human tissues that will change the manner in which studies of tissue function, microbiome influence, and drug effect are performed. Recent progress in organotypic culture of colonic epithelial stem cells has made it possible to create long-lived spheroids in a gelatinous matrix. However, the absence of chemical gradients as well as patterned physical support results in a disorganized and chaotic conformation that poorly mimics the structure and function of the colon, and furthermore is not amenable to microbiome co-culture. We propose to develop a novel microfabricated system that will enable ex vivo culture of human colonic epithelium and overlying microbiota that recapitulates the 3D structure and environment of the colonic mucosa in a setting which lies between an unpolarized cell culture system and the complexity of the intact human organism. Recent technical advances from our labs in sustained monolayer culture of colonic epithelial stem cells will be integrated with microfabricated scaffoldings and devices to create the colonic simulacrum. A number of innovations will be incorporated into the microengineered system with the goal of recapitulating the colonic stem-cell niche, the differentiated intestinal mucosa, the microbiota, and the dynamic information flow between these compartments. The platform will permit tight control of the luminal and basal crypt environments by providing independent fluidic and gaseous access to these compartments. The platform will support formation of mitogen, morphogen, differentiation-factor, dietary-compound and gaseous gradients to enable unprecedented investigations into colonic physiology. A number of hypotheses related to the interplay of dietary factors, the microbiome and the colonic epithelium will be tested to demonstrate the power and broad applicability of this transformative technology.

 描述（由应用程序提供）：在当前应用中，提出了一个合作的，多学科的研究项目，该项目有可能为健康和疾病中人类生理学研究创建新的范式。将开发一个最先进的微型制造平台，以创建人类结肠上皮及其相关的微生物组的功能性，体外复制品，即Simulacrum。这项新技术将用于对目前无法进行的肠道生理学进行新颖的研究和假设检验。此外，此处开发的技术和协议将建立从正常和解散的原发性人体组织中创建器官模拟的基础，这些器官将改变组织功能，微生物组影响和药物效应的研究方式。结肠上皮干细胞有机培养的最新进展使得在胶质基质中创建长寿命的球体成为可能。然而，没有化学梯度以及图案化的物理支持会导致一个混乱且混乱的会议，该会议模仿了结肠的结构和功能，而且不适合微生物组的共同培养。我们建议开发一种新型的微生物系统，该系统将使人类结肠上皮的离体培养和上覆盖的微生物群，该系统在不固定的细胞培养系统与完整的人体生物的复杂性之间介绍了结肠粘膜的3D结构和环境。我们实验室在持续的结肠上皮干细胞持续单层培养物中的技术进步将与微生物的脚手架和装置集成在一起，以创建结肠仿真。许多创新将纳入微型工程系统，目的是概括结肠干细胞生态位，分化的肠粘膜，微生物群和这些隔室之间的动态信息流。该平台将通过提供独立的流体和气态进入这些隔室的方式来严格控制腔和基本加密环境。该平台将支持有丝分裂原，形态学，分化因子，饮食化合物和气态梯度的形成，以实现对结肠生理学的前所未有的研究。许多与饮食因素相互作用，微生物组和结肠上皮相关的假设将进行测试，以证明这种变革性技术的功能和广泛适用性。