Development of Human Intestinal Simulacra

人体肠道模拟物的开发

基本信息

批准号：
9767231
负责人：
Nancy L. Allbritton
金额：
$ 37.37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767231
关键词：
3-Dimensional Achievement Adherent Culture Anaerobic Bacteria Architecture Area Bacteria Behavior Biological Assay Biological Models Biology Biopsy Butyrates Caliber Cardiovascular Diseases Cell Compartmentation Cell Culture System Cell Death Cell Differentiation process Cell physiology Cells Chemicals Coculture Techniques Colon 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 Hydrogels Immune Tolerance In Vitro Individual Interdisciplinary Study Intestinal Diseases Intestinal Mucosa Intestines Investigation Length Light Link Liquid substance Logistics Mediating Medicine Metabolic Metagenomics 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 autism spectrum disorder bacterial community base bone morphogenic protein colon microbiota community living dysbiosis genome wide association study gut microbiota human disease human stem cells human tissue innovation insight intestinal epithelium metabolomics metatranscriptomics microbiome microbiota model development monolayer morphogens mouse model mucosal microbiota new technology novel prevent public health relevance scaffold self-renewal stem stem cell differentiation stem cell niche three dimensional structure tool

项目摘要

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（由申请人提供）：在当前的申请中，提出了一个协作的、多学科的研究项目，该项目有潜力为人类健康和疾病生理学研究创造一个新的范例，一个最先进的微制造平台。将开发出人类结肠上皮及其相关微生物组的功能性体外复制品，即模拟物。这项新技术将用于进行肠道生理学的新颖研究和假设检验。此外，这里开发的技术和方案将为从正常和患病的原代人体组织中创建器官模拟奠定基础，这将改变组织功能、微生物组影响和药物作用研究的最新进展。在结肠上皮干细胞的器官型培养中，可以在凝胶状基质中创建长寿的球体，然而，化学梯度和图案化物理支撑的缺乏导致了无序和混乱的构象。不能很好地模拟结肠的结构和功能，而且不适合微生物组共培养，我们建议开发一种新型微加工系统，该系统将能够对人类结肠上皮和覆盖的微生物群进行离体培养，从而概括结肠的 3D 结构和环境。结肠粘膜处于非极化细胞培养系统和完整人体有机体的复杂性之间，我们实验室在结肠持续单层培养方面取得了最新技术进展。上皮干细胞将与微型支架和装置集成，以创建结肠模拟物。微工程系统将融入许多创新技术，目的是重现结肠干细胞生态位、分化的肠粘膜、微生物群和结肠模拟物。这些隔间之间的动态信息流将通过提供对这些隔间的独立流体和气体通道来严格控制管腔和基底隐窝环境。丝裂原、形态发生素、分化因子、膳食化合物和气体梯度，以便对结肠生理学进行前所未有的研究。将测试与饮食因素、微生物组和结肠上皮相互作用相关的许多假设，以证明其效力和广泛的适用性。这项变革性技术。