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Intestinal Organoids as a model system for studying enteric disease

肠类器官作为研究肠道疾病的模型系统

基本信息

批准号：
8856069
负责人：
Alison A. Weiss
金额：
$ 93.13万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856069
关键词：
Address Advanced Development Age Animal Model Award Basic Science Biological Biological Models Carcinogens Clostridium difficile Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Communities Disease Educational Activities Engineering Enteral Epithelial Epithelium Escherichia coli Escherichia coli EHEC Escherichia coli Infections Evaluation Funding Gastrointestinal Diseases Goals Grant Helicobacter Infections Helicobacter pylori Human Immune response In Vitro Infection Intestines Methodology Modeling Molecular Morbidity - disease rate Organoids Pathogenesis Pathology Pathway interactions Patient Rights Physiology Process Proteins Reagent Recruitment Activity Reporter Research Research Personnel Research Project Grants Risk Factors Role Stomach Structure System Technology Tetracyclines Therapeutic Time Tissues Toxin Training Activity age related enteric pathogen gastrointestinal gastrointestinal infection human disease insight interest meetings member mortality novel novel therapeutics pathogen product development public health relevance research and development response small hairpin RNA stem cell fate

项目摘要

DESCRIPTION OF THE OVERALL U19 APPLICATION (provided by applicant): This proposal will use human gastrointestinal organoids as a model system. We will integrate state-of-the-art methodologies, with collaborative and synergistic research approaches to the study of gastrointestinal diseases. We will develop in vitro gastrointestinal models that replicate the biological structures of the human intestinal tract. These tissues will recapitulate human physiology and disease pathology, and incorporate components critical to disease and human host response. Our focus will span the pipeline from basic research (pathogenesis) to product development. For gastrointestinal pathogens that have no relevant animal models, another long-term goal is to develop model systems that can be used in IND-enabling studies. We will advance the field through the following Specific Aims: Aim 1. Title: Mechanisms of H. pylori-host infection using human gastric organoids. Research Project 1 will use the newly developed gastric organoid system to study Helicobacter pylori. The proposed studies have the potential to advance our understanding of the mechanisms by which H. pylori alters gastric stem cell fate, and advance our understanding of the role of H. pylori as a carcinogen. Aim 2. Title: Human Intestinal Organoids to Study Toxigenic Bacterial Pathogens. Research Project II will use human intestinal organoids as a novel model system to study two toxigenic enteric pathogens, Clostridium difficile and Shiga toxin (Stx) producing Escherichia coli (STEC). The proposed studies have the potential to advance our understanding of the pathogenic processes of C. difficile and STEC and create model systems for the evaluation of potential therapeutics. Aim 3. Title: Human gastroids and colonoids as 4D models of gastrointestinal infection. Research Project III will develop ex vivo models to determine age-dependent and temporal GI epithelial responses to: a) H. pylori infection in human gastric organoids (HGOs) and gastroids and b) Clostridium difficile (CD) and Shiga toxin-producing Escherichia coli (STEC) infection and their major toxins in human colonic organoids (HCOs) and colonoids. Aim 4. Technology dissemination. We will advance and encourage educational and training activities to investigators currently affiliated with this proposal, investigators funded through other NAMSED awards, and interested members of the scientific community in general. Aim 5. Organoid Engineering Core. The human organoid core will develop reporter lines in which fluorescent proteins are expressed in specific lineages. shRNA knockdown and CRISPR targeted lines will give rise to human gastro-intestinal organoids lacking specific lineages, and tetracycline-regulated systems will be used to expand specific lineages.