Polyamine Dysregulation in the Gastric Epithelium during Helicobacter pylori Infection and its Impact on Gastric Carcinogenesis

幽门螺杆菌感染期间胃上皮多胺失调及其对胃癌发生的影响

• 批准号: 10604957
• 负责人: Kara McNamara
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604957
• 关键词: Ablation; Acrolein; Adenocarcinoma; Adenocarcinoma Cell; Aldehydes; Amino Acids; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Atrophic Gastritis; Attenuated; Back; Cancer Etiology; Carcinoma; Catabolism; Cells; Cessation of life; Chemicals; Chronic; Chronic Gastritis; Correa cascade; Critical Pathways; DNA Damage; Data; Development; Disease Progression; Dysplasia; Enzymes; Epithelial Cells; Epithelium; Eukaryotic Initiation Factors; Exhibits; Failure; Future; Gastric Adenocarcinoma; Gastric Intraepithelial Neoplasia; Gastric Tissue; Gastric mucosa; Gastrins; Gastritis; Generations; Gerbils; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; Histologic; Human; Immune response; Infection; Infection Control; Inflammation; Insulin; Intestinal Metaplasia; Knockout Mice; Lesion; Macrophage; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Messenger RNA; Metabolic; Metabolism; Metaplasia; Mucosal Immune Responses; Mus; Oncogenic; Organoids; Pathway interactions; Patients; Persons; Polyamines; Population; Post-Translational Protein Processing; Principal Investigator; Propanolamines; Protein Translation Pathway; Proteins; Proteomics; Publishing; Putrescine; Research; Risk; Risk Factors; Role; Signal Transduction; Spermidine; Spermine; Stomach; Stomach Carcinoma; Stomach Diseases; Supplementation; Testing; Tissues; Training; Transgenic Organisms; Translations; Up-Regulation; Wild Type Mouse; Work; beta catenin; cancer risk; carcinogenesis; carcinogenicity; career; cell growth; deoxyhypusine monooxygenase; deoxyhypusine synthase; experimental study; gastric cancer prevention; gastric carcinogenesis; gastric organoids; hypusine; inhibitor; interest; malignant stomach neoplasm; mouse model; novel; novel strategies; novel therapeutic intervention; polyamine oxidase; premalignant; response; targeted treatment; therapeutic target; transcriptome; translational goal; tumorigenesis

PROJECT SUMMARY Helicobacter pylori colonizes the stomach of about 50% of the world’s population and is the strongest known risk factor for developing gastric cancer, the fourth most common cause of cancer related deaths. Failure of the host response to control the infection leads to persistent inflammation, which initiates disease progression from chronic gastritis through a histological “Correa Cascade” that results in gastric carcinoma in 1-3% of all those infected. Due to antibiotic resistance, and the fact that antibiotic treatment may not be effective in reducing cancer risk once precancerous lesions are present, we need to develop new therapeutic strategies to limit progression to dysplasia and carcinoma. Our lab investigates the role of the polyamines, putrescine, spermidine, and spermine in gastric inflammation and carcinogenesis. Putrescine is sequentially converted to spermidine and spermine, which is back-converted to spermidine by spermine oxidase (SMOX). We have shown that SMOX expression is elevated in human and mouse gastric tissues infected with H. pylori. Furthermore, infected C57BL/6 Smox–/– mice exhibit depleted spermidine levels, and a decrease in gastritis and carcinogenic signaling compared to wild-type mice. Using FVB/N INS-GAS mice prone to developing gastric dysplasia and intramucosal carcinoma with H. pylori infection, we have seen that Smox–/– mice infected with H. pylori exhibit a significant reduction in gastric intramucosal carcinoma and extent of dysplasia. Spermine catabolism by SMOX generates 3-aminopropanol, which can spontaneously form acrolein, a reactive electrophilic aldehyde that has the potential to damage DNA and proteins. Our preliminary findings demonstrate that acrolein is produced in gastric tissues of H. pylori-infected FVB/N INS-GAS mice and is significantly reduced in Smox–/– FVB/N INS-GAS mice. Additionally, spermidine is an essential substrate for the synthesis of hypusine, a unique amino acid that is only found in the protein eukaryotic translation initiation factor 5A (EIF5A) by the action of the enzyme deoxyhypusine synthase (DHPS). Our recent work with human gastric organoids has revealed induction of hypusinated EIF5A levels with H. pylori infection, which was ablated with the chemical inhibitor of the pathway. Proteomic analysis on these organoids implicated hypusination as a critical pathway for oncogenesis. Taken together, we hypothesize that polyamine dysregulation due to SMOX activity in H. pylori-infected gastric epithelial cells leads to the generation of spermidine and acrolein, and upregulation of the hypusination pathway resulting in increased risk for gastric cancer development. Our specific aims are to determine: 1) the role of SMOX activity in gastric carcinogenesis, including effects of spermidine, spermine and acrolein in FVB/N INS-GAS mice. 2) if spermidine generated by SMOX contributes to gastric cancer development through hypusination using studies in human gastric organoids and mice with an epithelial-specific deletion of Dhps. This proposal seeks to elucidate the mechanisms by which SMOX induces gastric disease progression, thus identifying novel pathways to be targeted for therapeutic benefit, while providing the ideal training for my future career as a principal investigator.

项目概要 幽门螺杆菌寄居在世界上约 50% 人口的胃中，是已知的最强风险 胃癌是导致癌症相关死亡的第四大常见原因。主机故障 控制感染的反应会导致持续的炎症，从而引发疾病进展 慢性胃炎通过组织学“Correa Cascade”导致 1-3% 的人罹患胃癌 已感染。由于抗生素耐药性，以及抗生素治疗可能无法有效减少癌症 一旦出现癌前病变，我们需要制定新的治疗策略来限制进展 发育不良和癌。我们的实验室研究了多胺、腐胺、亚精胺和 精胺在胃炎症和癌变中的作用。腐胺依次转化为亚精胺和 精胺，通过精胺氧化酶 (SMOX) 反向转化为亚精胺。我们已经证明 SMOX 在感染幽门螺杆菌的人和小鼠胃组织中表达升高。此外，感染 C57BL/6 Smox–/– 小鼠表现出亚精胺水平耗尽，胃炎和致癌信号传导减少 与野生型小鼠相比。使用容易发生胃发育不良和粘膜内病变的 FVB/N INS-GAS 小鼠 幽门螺杆菌感染的癌症，我们发现感染幽门螺杆菌的 Smox–/– 小鼠表现出显着的 减少胃粘膜内癌和不典型增生的程度。 SMOX 分解代谢产生精胺 3-氨基丙醇，可以自发形成丙烯醛，一种具有潜在活性的反应性亲电子醛 破坏DNA和蛋白质。我们的初步研究结果表明丙烯醛是在胃组织中产生的 幽门螺杆菌感染的 FVB/N INS-GAS 小鼠中的 H. pylori 感染的比例显着降低，并且在 Smox–/– FVB/N INS-GAS 小鼠中显着减少。 此外，亚精胺是合成马尿嘧啶的重要底物，马尿嘧啶是一种独特的氨基酸，仅在 通过脱氧马尿苷酶的作用在蛋白质真核翻译起始因子 5A (EIF5A) 中发现 合酶（DHPS）。我们最近对人胃类器官的研究揭示了 hypuslated EIF5A 的诱导 幽门螺杆菌感染的水平已被该途径的化学抑制剂消除。蛋白质组分析 对这些类器官的研究表明，催眠作用是肿瘤发生的关键途径。综合起来，我们 假设幽门螺杆菌感染的胃上皮细胞中 SMOX 活性导致多胺失调，导致 亚精胺和丙烯醛的产生，以及催眠途径的上调，导致增加 胃癌发展的风险。我们的具体目标是确定：1​​）SMOX 活性在胃中的作用 致癌作用，包括亚精胺、精胺和丙烯醛对 FVB/N INS-GAS 小鼠的影响。 2) 如果是亚精胺 人类研究显示，SMOX 产生的 hypusination 会通过催眠作用促进胃癌的发展 胃类器官和具有上皮特异性 Dhps 缺失的小鼠。该提案旨在阐明 SMOX 诱导胃病进展的机制，从而确定新的靶向途径 以获得治疗效果，同时为我未来作为首席研究员的职业生涯提供理想的培训。