Project 1: Biomimetic Interactions Between Bacterial Pathogens and the Gastrointestinal Epithelium

项目1：细菌病原体与胃肠道上皮之间的仿生相互作用

基本信息

批准号：
10191937
负责人：
MANUEL R AMIEVA
金额：
$ 33.08万
依托单位：
STANFORD UNIVERSITY
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 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10191937
关键词：
3-Dimensional Address Adult Affect Air Animals Antibiotic Resistance Apical Bacteria Biomimetics CRISPR/Cas technology Cancer Etiology Cell Differentiation process Cell surface Cells Cessation of life Chronic Comparative Study Confocal Microscopy Data Set Disease Disease Progression Epithelial Epithelial Cells Exposure to Feedback Gastric Glands Gastroenteritis Generations Genetic Screening Gland Growth Helicobacter Infections Helicobacter pylori Human Imaging Techniques Immune Immune response Immune system Infection Inflammation Inflammatory Information Dissemination Innate Immune Response Intestines Invaded Lead Liquid substance Lung Methods Modeling Molecular Mucosal Immune System Mucositis Mucous Membrane Mucous body substance Occupational activity of managing finances Organoids Pathologic Pathway interactions Peptic Ulcer Population Public Health Reporter Reporting Research Resistance Resolution Resources Risk Factors Role Salmonella Salmonella typhi Screening procedure Side Site Stains Stomach Surface Suspension Culture Suspensions Swimming Testing Therapeutic Tissue Engineering Typhoid Fever Vaccines Virulence Factors Virus adaptive immune response colonization resistance gastric organoids gastrointestinal gastrointestinal epithelium genetic manipulation human tissue immune activation intestinal epithelium live cell imaging malignant stomach neoplasm mutant novel pathogen pathogenic bacteria preservation response single-cell RNA sequencing socioeconomics stem cells synergism targeted treatment tool development

项目摘要

PROJECT SUMMARY (Project 1) Helicobacter pylori and Salmonella enterica serovar Typhi (Typhi) are both strictly human-adapted pathogens that colonize the stomach and intestine and are major public health threats worldwide that disproportionally affect populations with lower socioeconomic resources. H. pylori chronically infects over 50% of the world population and is the main risk factor for peptic ulcers and gastric cancer. About 77% (812,000) of new cases of gastric cancer were attributable to H. pylori in 2018 (GLOBOCAN). Gastric cancer is the 3rd leading cause of cancer death worldwide with about 783,000 deaths reported in 2018 (WHO). Typhi infects more than 20 million people yearly and causes over 500,000 deaths annually from Typhoid fever. Both H. pylori and Salmonella have evolved molecular adaptations to chronically colonize human mucosal surfaces and evade clearance from host innate and adaptive immune responses. In addition, both are becoming increasingly difficult to treat because of rising antibiotic resistance and poor understanding of their persistence mechanisms. We will address these emerging problems by leveraging novel biomimetic platforms of human-derived gastric and intestinal organoids including 1) a method to reverse the polarity and control the differentiation of three-dimensional epithelial organoids in suspension to expose the apical surface for infection studies, 2) a method to induce differentiation of intestinal microfold (M) cells, and 3) an air-liquid interface culture method to preserve the endogenous mucosal immune system. We will use these platforms to address difficult-to-model problems, including: 1) defining and manipulating critical niches that enable bacterial colonization of the epithelial surface, 2) elucidating specialized sites of invasion and intracellular replication in the mucosa, and 3) understanding secondary activation of immune responses and immune feedback on the epithelium that control bacterial colonization and disease progression. These studies will lead to the identification of new pathways that could serve as novel targets for decolonization, therapeutics, and vaccine strategies.

项目概要（项目 1）幽门螺杆菌和伤寒沙门氏菌都是严格意义上的人类适应病原体它们在胃和肠道中定植，是全世界主要的公共卫生威胁，对健康产生了不成比例的影响社会经济资源较低的人群。幽门螺杆菌长期感染世界 50% 以上的人口是消化性溃疡和胃癌的主要危险因素。约 77%（812,000）的胃病新病例 2018 年癌症归因于幽门螺杆菌 (GLOBOCAN)。胃癌是第三大癌症原因 2018 年全球报告死亡人数约为 783,000 人（世界卫生组织）。伤寒感染超过 2000 万人每年有超过 50 万人死于伤寒。幽门螺杆菌和沙门氏菌均已进化分子适应长期定殖于人类粘膜表面并逃避宿主先天清除和适应性免疫反应。此外，由于死亡率上升，两者都变得越来越难以治疗。抗生素耐药性和对其持久性机制的了解不足。我们将解决这些新兴的通过利用人源胃和肠类器官的新型仿生平台来解决问题，包括 1）一种反转极性并控制三维上皮类器官分化的方法悬浮液暴露顶端表面进行感染研究，2）诱导肠道分化的方法微折叠（M）细胞，3）气液界面培养方法，以保护内源性粘膜免疫系统。我们将使用这些平台来解决难以建模的问题，包括：1）定义和操纵使细菌能够在上皮表面定植的关键生态位，2）阐明专门的粘膜中的侵袭和细胞内复制位点，以及 3) 了解控制细菌定植和疾病的上皮细胞的免疫反应和免疫反馈进展。这些研究将导致确定新的途径，这些途径可以作为新的目标非殖民化、治疗和疫苗策略。