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.

项目摘要 幽门螺杆菌在世界上约50%的人口的胃中定植，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 控制感染的反应导致持续性炎症，这引发疾病进展， 慢性胃炎通过组织学的“Correa级联反应”，导致胃癌的1-3%， 感染了由于抗生素耐药性，以及抗生素治疗可能无法有效减少癌症的事实， 一旦出现癌前病变，我们需要开发新的治疗策略来限制进展 发育异常和癌症。我们的实验室研究了多胺，腐胺，亚精胺， 精胺在胃炎症和癌变中的作用腐胺依次转化为亚精胺， 精胺，其通过精胺氧化酶（SMOX）反向转化为亚精胺。我们已经证明，SMOX 在感染H.幽门。此外，感染 C57 BL/6 Smox-/-小鼠表现出精脒水平耗尽，胃炎和致癌信号减少 与野生型小鼠相比。使用FVB/N INS-GAS小鼠，易于发生胃发育不良和粘膜内 癌伴H. pylori感染，我们已经看到Smox-/-小鼠感染H.幽门螺杆菌表现出显著的 减少胃粘膜内癌和异型增生的程度。通过SMOX生成精胺催化剂 3-氨基丙醇，其可以自发地形成丙烯醛，丙烯醛是一种反应性亲电子醛，具有潜在的 破坏DNA和蛋白质。我们的初步研究结果表明，丙烯醛是产生在胃组织 阁下于在Smox-/- FVB/N INS-GAS小鼠中显著降低。 此外，亚精胺是合成羟腐胺赖氨酸的必需底物，羟腐胺赖氨酸是一种独特的氨基酸， 在蛋白质真核翻译起始因子5A（EIF 5A）中通过脱氧羟腐胺赖氨酸酶的作用发现 合成酶（DHPS）。我们最近对人类胃类器官的研究揭示了羟腐胺赖氨酸化EIF 5A的诱导作用。 水平与H。幽门螺杆菌感染，这是消融与化学抑制剂的途径。蛋白质组学分析 在这些类器官上暗示hypusination是肿瘤发生的关键途径。总之，我们 假设在H.幽门感染的胃上皮细胞 亚精胺和丙烯醛的产生，以及羟腐胺赖氨酸化途径的上调， 胃癌的发病风险。我们的具体目标是确定：1）SMOX活性在胃粘膜中的作用， 致癌作用，包括亚精胺、精胺和丙烯醛在FVB/N INS-GAS小鼠中的作用。2)如果亚精胺 SMOX通过羟腐胺酸化促进胃癌的发展 胃类器官和具有Dhps的上皮特异性缺失的小鼠。本建议旨在阐明 SMOX诱导胃病进展的机制，从而确定新的靶向途径 为了治疗的好处，同时为我未来作为主要研究者的职业生涯提供理想的培训。