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 幽门螺杆菌在世界人口的大约50％的loonache上定居，是已知风险的强烈风险 主机的失败 对控制感染的反应导致持续感染，这引发了疾病的进展 慢性胃炎通过组织学“ Correa级联”，在所有这些导致胃癌中导致胃癌 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的事实 风险一旦存在癌前病变，我们就需要制定新的治疗策略以限制进展 发育不良和癌。我们的实验室调查了多胺，prescine，Permidine和 胃感染和癌变中的精子。腐腐是依次转换为精子定和 精子，通过精子氧化酶（SMOX）将其反转转至精子。我们已经证明了Smox 感染幽门螺杆菌的人和小鼠胃组织中的表达升高。此外，被感染 C57BL/6 SMOX - / - 小鼠暴露了脱离的精子水平，胃炎和致癌信号的降低 与野生型小鼠相比。使用容易发生胃发育不良和粘膜内的FVB/N INS-GAS小鼠 患有幽门螺杆菌感染的癌，我们已经看到，幽门螺杆菌感染的Smox - / - 小鼠暴露了显着 胃内癌和发育不良程度的降低。 Smox生成的精子分解代谢 3-氨基丙醇可以赞助，这是一种具有电势的反应性亲电醛 损害DNA和蛋白质。我们的初步发现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小鼠的大量显着降低了SMOX - / - FVB/N INS-GAS小鼠。 另外，精子是合成dryusine的必不可少的底物，该蛋白是一种独特的氨基酸，仅是 通过酶脱氧蛋白的作用在蛋白质真核翻译起始因子5a（EIF5A）中发现 合酶（DHP）。我们最近与人类胃癌的工作揭示了诱导无偶然的EIF5A 幽门螺杆菌感染的水平，该水平与该途径的化学抑制剂消融。蛋白质组学分析 在这些类器官上，实施了非胰岛，作为肿瘤发生的关键途径。总的来说，我们 假设由于幽门螺杆菌感染的胃皮细胞中Smox活性引起的多胺失调导致 为精子和丙烯醛的产生，以及无偶然途径的上调，导致增加 胃癌发展的风险。我们的具体目的是确定：1​​）SMOX活性在胃中的作用 致癌作用，包括精子，精子和丙烯醛在FVB/N INS-GAS小鼠中的作用。 2）如果精子定 由SMOX产生的通过人类研究的研究来促进胃癌的发展 胃癌和小鼠具有DHP的上皮特异性缺失。该建议旨在阐明 SMOX诱导胃病进展的机制，从而确定了目标的新途径 为了治疗益处，同时为我作为首席研究员的未来职业提供理想的培训。