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: 10220023
• 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/10220023
• 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; 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; 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; gastric corpus; gastric organoids; 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.

项目总结/摘要 该申请提出了一个为期五年的研究职业发展计划，重点是主机和 微生物因素，有助于胃化生。探索主机和主机的综合方法 化生环境的细菌决定因素将增强我们对动态相互作用的全面理解。 从而建立了胃癌前状态候选人目前是一名医学讲师， 华盛顿大学医学院胃肠病学分部。该提案是对 候选人以前的工作证明了幽门螺杆菌利用化生变化的能力， 来扩大自己的利基市场拟议的实验将结合胃上皮生物学专业知识， 候选人的导师Jason米尔斯博士，以及幽门螺杆菌诱变经验， 候选人的共同导师里克·皮克博士总之，候选人将处于独特的地位，以获得新的技能 集和扩大以前开发的技术，这将使他能够开拓出一个独特的利基内， 领域和过渡到一个独立的医生科学家。 胃癌仍然是全球癌症相关死亡的主要原因之一。慢性感染 胃适应性细菌幽门螺杆菌代表了最重要的风险因素， 进展为胃癌。在慢性炎症的情况下，分泌酸的壁细胞的损失， 胃体刺激胃体腺的重组，其特征在于增加的增殖 的胃祖细胞和有丝分裂后的主细胞在腺基部重新编程成一个群体， 增生性化生细胞，我们称之为褐变。我们最近证明， 幽门螺杆菌利用这些化生腺体的变化，扩大其在胃的定植， 这是已知的赋予额外的致癌风险。该提案描述了一种双重方法， 鉴定和表征有助于建立该系统的宿主和微生物因素， 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个组分， I IFN/dsRNA信号通路在两种不同的胃化生模型中上调。我们将 剖析这种高度保守的抗病毒途径在以前未表征的胃肠道疾病中的作用， 化生类似地，我们的目的是证明在变斑过程中内源性dsRNA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，幽门螺杆菌特异性转录物， 在胃体中差异表达。使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肠道定植的背景下验证和表征这些基因， 胃上皮化生的形成。综上所述，该提案旨在确定微生物 预后指标和潜在的治疗干预领域的发展胃化生。