Project 1: Effect of Iron Deprivation on H. pylori-induced Gastric Carcinogenesis

项目1：缺铁对幽门螺杆菌诱发的胃癌的影响

• 批准号: 10581607
• 负责人: RICHARD M. PEEK
• 金额: $ 32.3万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581607
• 关键词: Acceleration; Acute; Address; Biopsy; Cancer Etiology; Cancer Model; Cells; Cessation of life; DNA Damage; DNA Sequence Alteration; Development; Dietary Factors; Disease; EGFR gene; Endoscopy; Epithelial Cells; Epithelium; Event; Exhibits; Gastric Adenocarcinoma; Gastritis; Genetic Transcription; Gerbils; Harvest; Helicobacter Infections; Helicobacter Pylori-Related Malignant Neoplasm; Helicobacter pylori; Helicobacter pylori induced carcinogenesis; High grade dysplasia; Human; Hyperplasia; Immunoglobulin Domain; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Integration Host Factors; Iron; Knowledge; Lesion; Leucine-Rich Repeat; Link; Malignant Neoplasms; Modeling; Mucous Membrane; Mus; Neoplasms; Oncogenic; Oncoproteins; Pathogenesis; Pathogenicity; Patients; Persons; Pilum; Positioning Attribute; Predisposition; Proliferating; Proteins; Proteomics; Risk Factors; Rodent Model; Role; Signal Induction; Signal Transduction; Stomach; Structure; System; Testing; Type IV Secretion System Pathway; Virulence; beta catenin; cancer risk; carcinogenesis; carcinogenicity; cell type; cytokine; deprivation; differential expression; epithelial stem cell; epithelium regeneration; gastric carcinogenesis; gastric organoids; genome sequencing; high risk; innovative technologies; iron deficiency; malignant stomach neoplasm; metabolomics; microbial; mouse model; mutant; novel; overexpression; premalignant; response; self organization; stem cell biomarkers; stem cell homeostasis; stem cell niche; stem cell population; stem cells; whole genome

Project 1 Summary H. pylori is the strongest known risk factor for gastric cancer. One H. pylori determinant that augments cancer risk is the cag type IV secretion system (T4SS) which exports an oncoprotein, CagA, into host epithelial cells. A host molecule that influences gastric cancer in conjunction with H. pylori is ß-catenin, which tightly regulates stem cell homeostasis; correspondingly, aberrant ß-catenin signaling within a susceptible stem cell population may lower the threshold for carcinogenesis. A specific stem cell marker in the stomach is Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), a pan-ERBB regulator, and targeted activation of ß-catenin within Lrig1+ cells leads to the development of hyperplasia, hyperproliferation, and high-grade dysplasia in the stomach. Our group has now infected mouse and human gastroids to demonstrate that H. pylori can activate ß- catenin and drive proliferation, expansion, and functional activation of Lrig1+ cells in a cag T4SS-dependent manner. Another cag T4SS-dependent carcinogenic response occurs within the context of iron deficiency and we have shown that iron depletion enhances the ability of H. pylori to colonize the gastric stem cell niche, to activate ß-catenin, and induce injury in mice. In studies performed with Core A, we demonstrated that iron depletion accelerates carcinogenesis in H. pylori-infected Mongolian gerbils in a cagA-dependent manner. With Project 3, we demonstrated that H. pylori harvested from iron-deficient gerbils exhibit an enhanced capacity to assemble cag T4SS-associated pili, translocate CagA, and induce expression of proinflammatory cytokines. Proteomics and metabolomics studies performed with Cores B and C and whole genome sequencing performed with Projects 2 and 3 have identified a focused subset of differentially expressed proteins, metabolites, and genetic mutations, respectively, among H. pylori strains isolated from iron-deficient versus iron-normal gerbils as well as humans with premalignant lesions. Our hypothesis is that specific interactions between H. pylori and Lrig1 progenitor cells contribute to augmentation in cancer risk conferred by cag+ strains within the context of iron deficiency. Thus, our specific aims are to: 1. Utilize mouse models and gastroids to define the role of Lrig1 and new effectors in regulating oncogenic epithelial responses to H. pylori cag+ carcinogenic strains. 2. Define the role of iron deficiency and Lrig1 in pathogenesis using H. pylori-infected gastroids and ß- catenin over-expressing mouse models. 3. Utilize rodent models and H. pylori mutant strains to inform mechanistic studies focused on microbial virulence constituents within the context of iron deficiency. !

项目1摘要 H.幽门螺杆菌是胃癌最强的已知危险因素。一个H幽门螺杆菌决定子，增强癌症 风险是cag IV型分泌系统（T4 SS），其将癌蛋白CagA输出到宿主上皮细胞中。一 与H.幽门螺杆菌是β-连环蛋白，它紧密调节 干细胞稳态;相应地，在易感干细胞群体中异常的β-连环蛋白信号传导 可能会降低致癌的门槛。胃中的一种特殊干细胞标记物是富含亮氨酸的重复序列 和免疫球蛋白样结构域1（Lrig 1），一种泛ERBB调节剂，以及靶向激活 Lrig 1+细胞可导致乳腺癌细胞增生、过度增生和高度发育不良。 胃我们的小组现在已经感染了小鼠和人类的胃，以证明H。pylori可以激活 在cag T4 SS依赖性细胞中，连环蛋白和驱动Lrig 1+细胞的增殖、扩增和功能活化。 方式另一种cag T4 SS依赖性致癌反应发生在缺铁的情况下， 我们已经表明铁的缺乏增强了H.幽门螺杆菌定植胃干细胞龛， 激活β-连环蛋白并诱导小鼠损伤。在对核心A进行的研究中，我们证明了铁 耗尽加速H. pylori感染的蒙古沙鼠的cagA依赖的方式。与 项目3，我们证明了H。从缺铁沙鼠中获得的幽门螺杆菌表现出增强的能力， 组装cag T4 SS相关的皮利，易位CagA，并诱导促炎细胞因子的表达。 使用Cores B和C以及全基因组测序进行蛋白质组学和代谢组学研究 与项目2和3一起进行的研究已经鉴定了差异表达蛋白质的集中子集， 代谢产物和遗传突变。幽门螺杆菌菌株分离自缺铁与 铁正常的沙鼠以及具有癌前病变的人类。我们的假设是特定的相互作用 H. pylori和Lrig 1祖细胞有助于增加cag+菌株引起的癌症风险 在缺铁的情况下。因此，我们的具体目标是： 1.利用小鼠模型和胃窦来确定Lrig 1和新效应物在调节 致癌上皮细胞对H. pylori cag+致癌菌株。 2.使用H定义铁缺乏和Lrig 1在发病机制中的作用。幽门螺杆菌感染的胃和幽门螺杆菌， 连环蛋白过表达小鼠模型。 3.利用啮齿动物模型和H.幽门螺杆菌突变株，以通知机制研究集中在微生物 缺铁背景下的毒力成分。 !