H pylori-host Interactions

幽门螺杆菌-宿主相互作用

• 批准号: 8856072
• 负责人: Yana Zavros
• 金额: $ 37.76万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8856072
• 关键词: 3-Dimensional; Abnormal Epithelial Cell; Acids; Address; Adult; Affect; Animal Model; Antral; Architecture; Bacteria; Behavior; Biological Assay; Biological Models; Cancer Etiology; Cancer cell line; Carcinogens; Cell Differentiation process; Cells; Cessation of life; Chronic; Data; Development; Diagnosis; Disease; Disease Progression; Embryonic Development; Endocrine; Enteral; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Event; FGF10 gene; Fundus; Gastric Glands; Gastric Tissue; Gastrins; Gastritis; Genetic; Gland; Goals; Helicobacter Infections; Helicobacter pylori; Human; Immune response; In Vitro; Individual; Infection; Inflammation; Intestines; Knowledge; Laboratories; Lesion; Malignant Neoplasms; Metaplasia; Mind; Modeling; Molecular; Molecular Profiling; Molecular Target; Morphology; Mucous body substance; Mus; Nature; Organ; Organogenesis; Organoids; Outcome; Pathogenesis; Pathology; Pathway interactions; Peptic Ulcer; Pluripotent Stem Cells; Property; Protocols documentation; Public Health; RNA Sequences; Research; Risk; Role; Severities; Signal Pathway; Signal Transduction; Somatostatin; Staging; Stem cells; Stomach; Stomach Diseases; Surface; Survival Rate; System; Techniques; Testing; United States; Virulence Factors; Work; base; cell type; cellular targeting; gastric foveola; gastric fundus; ghrelin; in vivo; innovation; insight; malignant stomach neoplasm; meetings; novel; novel strategies; prevent; progenitor; research study; response; species difference; stem cell fate; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Chronic gastric inflammation, typically caused by Helicobacter pylori (H. pylori), is the most consistent lesion leading to cancer. During a well-choreographed interaction between H. pylori and the host, the progression from chronic inflammation to cancer involves gastric epithelial changes with evidence of hyperproliferation and the disruption of normal gland morphology and differentiation. Although H. pylori virulence factors are known to interfere with signaling pathways in gastric epithelial cells, the identity of these target cells is unknown. Abnormal differentiation (metaplasia) is associated with cancer and seems to reflect a permanent alteration in the behavior of the stem cells, thus making the gastric stem cell a candidate H. pylori target. The objective of this proposal is to identify the underlying mechanism by which H. pylori-host interactions trigger the disruption of epithelial cell differentiation and thus the cascade leading to cancer. The acquisition of such knowledge is the first step in a continuum of research required to achieve our long-term goal that is to understand the pathogenesis of H. pylori-induced gastric cancer. The central hypothesis is that H. pylori primarily triggers hyperproliferation of the stem cell compartment in both the fundus and antrum leading to aberrant epithelial cell differentiation. Moreover we hypothesize that differences in fundic pathology triggered by H pylori are due to differences in target cell activation in the fundus versus antrum. The hypothesis has been formulated on the basis of preliminary studies produced in our laboratory demonstrating the first successful efforts to generate three-dimensional human gastric organoids (hGOs) de novo through directed differentiation of human pluripotent stem cells (hPSCs). hGOs are antral in nature and can be used to effectively model the early stages of H. pylori infection. The rationale for these studies is to acquire an understanding of the molecular mechanisms by which H. pylori infection colonizes the stomach and induces disease. Acquiring such knowledge may allow us to then develop techniques to disrupt bacterial colonization and thus prevent disease progression. Guided by strong preliminary data, this hypothesis is tested by pursuing two specific aims: 1) What are the primary H. pylori target cells during infection of the antrum? and 2) What are the molecular pathways that regulate development of fundic organoids? The hypothesis will be tested using genetic lineage tracing and single-cell RNA-sequencing. The research proposed is innovative, because it focuses on novel approaches that will allow us to assay changes in gastric epithelial cell proliferation and differentiation in relation to the direct interaction with H. pylori. Conceptually innovative, the current proposal will identify novel insights into the direct interaction between H. pylori and the host gastric epithelium independent of the immune response. Moreover the current study has the potential to advance our understanding of the mechanism by which H. pylori may alter the gastric stem cell fate. The proposed research is significant because it is expected to provide knowledge that is crucial to our understanding of the role of H. pylori as a carcinogen.

项目总结/摘要 慢性胃炎，通常由幽门螺杆菌（H。pylori），是最一致的病变 导致癌症在H。幽门螺杆菌和宿主的关系， 从慢性炎症到癌症涉及胃上皮细胞的变化，有过度增殖的证据， 正常腺体形态和分化的破坏。虽然H.已知幽门螺杆菌毒力因子 干扰胃上皮细胞中的信号传导途径，这些靶细胞的身份是未知的。 异常分化（化生）与癌症有关，似乎反映了细胞内的永久性改变。 干细胞的行为，从而使胃干细胞成为候选人H。pylori target.的目标 这一建议是为了确定H.幽门-宿主相互作用触发了 上皮细胞的分化，从而级联导致癌症。这种知识的获得是 这是实现我们长期目标所需的连续研究的第一步， 致病性H.幽门诱发胃癌中心假设是H.幽门螺杆菌主要触发 胃底和胃窦干细胞区室的过度增殖导致异常上皮细胞 分化此外，我们假设幽门螺杆菌引发的胃底病理差异是由于 胃底与胃窦中靶细胞活化的差异。这个假设是根据 在我们实验室进行的初步研究的基础上，首次成功地产生了 通过人的定向分化从头构建三维人胃类器官（hmos） 多能干细胞（hPSC）。阻滞本质上是窦性的，可用于有效地模拟早期 阶段H.幽门感染这些研究的基本原理是获得对分子生物学的理解。 H.幽门螺杆菌感染在胃中定植并诱发疾病。获取此类 这些知识可以使我们开发出破坏细菌定植的技术，从而预防疾病 进展在强有力的初步数据的指导下，通过追求两个具体目标来检验这一假设：1） 主要的H。幽门螺杆菌的目标细胞在感染的胃窦？2）分子结构是什么 调节胃底类器官发育的途径？这个假设将用遗传谱系来检验 追踪和单细胞RNA测序。该研究具有创新性，因为它侧重于新颖的 这些方法将使我们能够测定胃上皮细胞增殖和分化的变化， 与H的直接相互作用。幽门。从概念上讲，目前的提案将确定新的 对H.幽门螺杆菌和宿主胃上皮细胞的免疫无关 反应此外，目前的研究有可能通过以下方式促进我们对该机制的理解： 其中H。幽门螺杆菌可能改变胃干细胞的命运。这项研究的重要性在于， 提供对我们理解H的作用至关重要的知识。幽门螺杆菌是一种致癌物质。