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

• 批准号: 10614390
• 负责人: MANUEL R AMIEVA
• 金额: $ 36.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10614390
• 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 Cells; Epithelium; 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; Liquid substance; Lung; M cell; Methods; Modeling; Molecular; Mucosal Immune System; Mucositis; Mucous Membrane; Mucous body substance; Occupational activity of managing finances; Organoids; Pathologic; Pathway interactions; Peptic Ulcer; Persons; 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; Technology; 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; permissiveness; preservation; response; single-cell RNA sequencing; socioeconomics; stem cells; synergism; targeted treatment; tool development; vaccine strategy

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.

项目摘要（项目1） 幽门螺杆菌和沙门氏菌肠血清鼠伤寒（Typhi）都是严格的人类适应性病原体 在全球范围内殖民胃和肠子，是全球主要的公共卫生威胁 社会经济资源较低的人群。幽门螺杆菌长期感染超过50％的世界人口 是消化性溃疡和胃癌的主要危险因素。大约77％（812,000）新的胃病例 癌症归因于2018年幽门螺杆菌（Globocan）。胃癌是癌症的第三主要原因 全世界死亡，2018年报告约有783,000人死亡（WHO）。 Typhi感染了超过2000万人 每年一次，每年造成500,000多人死亡。幽门螺杆菌和沙门氏菌均进化 分子适应以长期定植人粘膜表面并从宿主先天逃避清除 和自适应免疫反应。此外，由于上升 抗生素的抗性和对其持久性机制的不良理解。我们将解决这些新兴 通过利用人类源自胃和肠癌的新型仿生平台的问题 1）扭转极性并控制三维上皮器官的方法 悬浮液以暴露顶部以进行感染研究，2）一种诱导肠道分化的方法 微量（M）细胞和3）一种空气界面培养方法，以保留内源性粘膜免疫 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 操纵能够使上皮表面细菌定殖的临界小境，2）阐明专业 粘膜中侵袭和细胞内复制的部位，3）了解 控制细菌定植和疾病的上皮的免疫反应和免疫反馈 进展。这些研究将导致确定可以作为新途径的新途径，这些途径可以作为新的目标 非殖民化，治疗和疫苗策略。