Establishing roles for the type I interferon/double-stranded RNA response and Helicobacter pylori-specific transcripts in the progression to metaplasia in gastric epithelium

确定 I 型干扰素/双链 RNA 反应和幽门螺杆菌特异性转录物在胃上皮化生进展中的作用

• 批准号: 9978060
• 负责人: Jose Bernardo Saenz
• 金额: $ 15.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978060
• 关键词: Acids; Address; Antiviral Agents; Area; Bacteria; Biology; Bone Marrow; Cancer Etiology; Cell Cycle; Cell Proliferation; Cells; Cessation of life; Chief Cell; Chimera organism; Chronic; Complement; Defect; Development; Dose; Double-Stranded RNA; Enzymes; Epithelial; Epithelium; Equilibrium; Gastric Adenocarcinoma; Gastric Metaplasia; Gastric Parietal Cells; Gastric mucosa; Gastroenterology; Gene Expression; Genes; Genetic Transcription; Gland; Glandular Metaplasia; Gram-Negative Bacteria; Helicobacter pylori; Histologic; Histopathology; Human; Immune; In Vitro; Infection; Inflammation; Injury; Interferon Type I; Interferon-alpha; Interferons; Medicine; Mentors; Metaplasia; Metaplastic Cell; Microarray Analysis; Mitotic; Modeling; Mus; Mutagenesis; Mutant Strains Mice; Nucleotide Biosynthesis; Oncogenic; Organoids; Pathway interactions; Physicians; Play; Population; Positioning Attribute; Preneoplastic Change; Preneoplastic Conditions; Process; Production; Prognostic Marker; Program Development; Purine Nucleotides; Purines; Pyloric antrum; Research; Risk; Risk Factors; Role; Scientist; Signal Pathway; Signal Transduction; Stomach; Techniques; Testing; Therapeutic Intervention; Transcript; Universities; Washington; Wild Type Mouse; Work; base; cancer risk; career development; chronic infection; clinical database; differential expression; experience; experimental study; in vivo; instructor; knock-down; malignant stomach neoplasm; medical schools; microbial; mutant; paligenosis; programs; receptor; repaired; response; response to injury; sensor; skills; stem cells; transcriptome sequencing

Project Summary/Abstract This application proposes a five year research career development program that focuses on the host and microbial factors that contribute to gastric metaplasia. The comprehensive approach of exploring the host and bacterial determinants of the metaplastic milieu will enhance our overall understanding of the dynamic interplay that establishes a gastric pre-neoplastic state. The candidate is currently an Instructor in Medicine in the Division of Gastroenterology at the Washington University School of Medicine. This proposal is an extension of the candidate’s previous work demonstrating the ability of Helicobacter pylori to exploit metaplastic changes in the host to expand its niche. The proposed experiments will incorporate gastric epithelial biology expertise from the candidate’s mentor, Dr. Jason Mills, as well as Helicobacter pylori mutagenesis experience from the candidate’s co-mentor, Dr. Rick Peek. Together, the candidate will be uniquely positioned to acquire new skill sets and expand on previously developed techniques that will allow him to carve out a unique niche within the field and transition to an independent physician scientist. Gastric cancer remains one of the leading causes of cancer-related deaths worldwide. Chronic infection with the stomach-adapted bacterium, Helicobacter pylori, represents the most significant risk factor for the progression to gastric cancer. In the setting of chronic inflammation, loss of acid-secreting parietal cells from the gastric corpus stimulates a reorganization of the corpus gland, characterized by an increased proliferation of gastric progenitor cells and a reprogramming of post-mitotic chief cells at the gland base into a population of proliferative metaplastic cells, a process that we have termed paligenosis. We recently demonstrated that Helicobacter pylori exploits these metaplastic glandular changes to expand its colonization of the gastric corpus, which is known to confer added oncogenic risk. This proposal describes a dual approach toward identifying and characterizing the host and microbial factors that contribute to the establishment of the metaplastic milieu. From the host perspective, a microarray analysis identified multiple components of the type I IFN/dsRNA signaling pathway that were upregulated in two distinct models of gastric metaplasia. We will dissect the role of this highly conserved antiviral pathway in the previously uncharacterized context of gastric metaplasia. Similarly, we aim to demonstrate that the accumulation of endogenous dsRNA during paligenosis serves as an intra-cellular signal for the development of gastric metaplasia. From the microbial perspective, a newly developed bacterial RNAseq analysis found Helicobacter pylori-specific transcripts that were differentially expressed in the gastric corpus. Using an established pipeline of in vivo and ex vivo experiments, we will validate and characterize these genes in the context of Helicobacter pylori’s colonization of the gastric corpus and establishment of gastric metaplasia. Taken together, this proposal seeks to identify microbial prognostic indicators and areas of potential therapeutic intervention in the development of gastric metaplasia.

项目摘要/摘要 本申请提出了一项为期五年的研究职业发展计划，重点是主持人和 导致胃化生的微生物因素。探索宿主的综合方法和 化生环境的细菌决定因素将增强我们对动态相互作用的整体理解 这建立了一种胃部肿瘤前状态。该候选人目前是该校的医学讲师。 华盛顿大学医学院胃肠病学部。这项提议是对 候选人之前的工作证明了幽门螺杆菌利用化生变化的能力 东道主要扩大自己的利基市场。拟议的实验将纳入来自 候选人的导师Jason Mills博士，以及幽门螺杆菌突变经验 候选人的共同导师里克·皮克博士。总之，候选人将在掌握新技能方面处于独特的地位 并在之前开发的技术上进行扩展，使他能够在 并过渡到独立的内科科学家。 胃癌仍然是全球癌症相关死亡的主要原因之一。慢性感染 胃适应细菌，幽门螺杆菌，是最重要的风险因素 进展为胃癌。在慢性炎症的背景下，分泌酸性的壁细胞从 胃体刺激体腺的重组，其特征是增殖增加。 胃祖细胞和腺基有丝分裂后主细胞的重新编程为 增生性化生细胞，我们称之为掌状突起。我们最近证明了 幽门螺杆菌利用这些化生的腺体变化来扩大其在胃的定植 语料库，这是已知的赋予额外的致癌风险。这项提案描述了一种双重方法，以 确定和表征宿主和微生物因素对建立 化生环境。从宿主的角度来看，微阵列分析确定了该类型的多种成分 IIFN/dsRNA信号通路在两种不同的胃化生模型中上调。我们会 解剖这一高度保守的抗病毒途径在以前未被描述的胃部疾病中的作用 化生。同样，我们的目的是证明内源性dsrna在帕金森病期间的积累。 作为胃化生发展的细胞内信号。从微生物的角度来看， 新开发的细菌RNAseq分析发现，幽门螺杆菌特异的转录本 在胃体差异表达。利用已建立的体内和体外实验管道， 我们将在幽门螺杆菌在胃中定植的背景下验证和表征这些基因 语料库与胃化生的建立。综上所述，这项提案试图识别微生物 胃化生发展中的预后指标和潜在的治疗干预领域。