Omega-3 derived epoxy fatty acids and sEH in pancreatitis-induced carcinogenesis

Omega-3 衍生的环氧脂肪酸和 sEH 在胰腺炎诱发的癌变中的作用

• 批准号: 9253390
• 负责人: Guang-Yu Yang
• 金额: $ 48.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-05 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253390
• 关键词: Acids; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Attenuated; Caerulein; Cell model; Chemopreventive Agent; Clinical; Colitis; Cyclooxygenase Inhibitors; Cytochrome P450; Data; Development; Docosahexaenoic Acids; Effectiveness; Eicosapentaenoic Acid; Ensure; Enzymes; Epoxide hydrolase; Epoxy Compounds; FAT gene; Fatty Acids; Glycols; Growth; Hemorrhage; Human; Hydrolase; Inflammation; Inflammatory; Knock-out; Life; Lipids; Lipoxygenase; Malignant neoplasm of pancreas; Mediator of activation protein; Metabolic Pathway; Metabolism; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Biology; Mus; NF-kappa B; Omega-3 Fatty Acids; Oral; Organ; PPAR gamma; Pancreatic Adenocarcinoma; Pancreatic carcinoma; Pancreatitis; Pharmaceutical Preparations; Physiological; Polyunsaturated Fatty Acids; Prevention strategy; Prostaglandin-Endoperoxide Synthase; Publishing; Risk Factors; Role; Sampling; Signal Transduction; Supplementation; Technology; Testing; Transgenes; Transgenic Mice; Ulcer; angiogenesis; cancer prevention; carcinogenesis; carcinogenicity; cardiovascular risk factor; chronic pancreatitis; data modeling; gastrointestinal; inhibitor/antagonist; macrophage; metabolomics; mouse model; mutant; nano; novel; overexpression; public health relevance; success

 DESCRIPTION (provided by applicant): The objective of this project is to determine the role of ω-3 derived epoxy fatty acid (ω-3 epoxides) and soluble epoxide hydrolase (sEH) in mutant Kras/pancreatitis-induced carcinogenesis and to establish an efficient strategy for the prevention of pancreatic cancer using ω-3 polyunsaturated fatty acids (PUFAs) and small molecular sEH inhibitors. Anti-inflammatory/carcinogenic effects of ω-3 PUFAs are well known; but the mechanism/s remains unclear. Of the three main metabolic pathways (COX, LOX, and CYP), ω-3 PUFAs are predominantly metabolized by CYP epoxygenase/s, leading to an accumulation of ω-3 epoxy fatty acid (ω-3 epoxides); and ω-3 PUFAs are poor substrates of COX and LOX. Fat1 transgenic mouse constitutively converts ω-6 to ω-3 PUFAs in all organs. Lipid metabolomics profiling in humans with ω-3 PUFAs supplementation and in Fat1 mice further demonstrate that ω-3 epoxides are major metabolites. Functional studies indicate that ω-3 epoxides are highly potent metabolites responsible for anti-inflammatory/carcinogenic actions, possibly via targeting inflammatory signals and MAP kinase. However, under physiologic conditions, these ω-3 epoxides are quickly inactivated by sEH to the diol products, and a sEH inhibitor appears crucial to stabilizing/enhancing these ω-3 epoxides actions. Thus, we hypothesize that ω-3 epoxides are the key metabolites of ω-3 PUFAs for inhibiting inflammation and carcinogenesis via targeting Kras-activated MAP kinases and inflammation signals (NF- kB and PPARγ), and that sEH inhibition is an efficient approach to enhance these ω-3 epoxides actions against pancreatitis-induced carcinogenesis. There are three specific Aims to test our hypothesis: 1) to determine a role of Fat1 transgene, sEH gene deficiency or their combination in stabilizing and enhancing ω-3 epoxides actions against mutant Kras/pancreatitis-induced carcinogenesis in PanKras mice, 2) to determine the effectiveness of the ω-3 PUFAs combined with a highly potent sEH inhibitor as an efficient chemopreventive approach against pancreatitis-induced carcinogenesis in PanKras mice, and 3) to test our hypothesis that ω-3 epoxides are the key metabolites of ω-3 PUFAs for inhibiting pancreatic cancer via targeting mutant Kras-activated signals, inflammation signals (NF-kB and PPARγ) and angiogenesis using our unique cell models and molecular biology approaches.

 描述（由申请人提供）：该项目的目的是确定 ω-3 衍生的环氧脂肪酸（ω-3 环氧化物）和可溶性环氧化物水解酶（sEH）在突变型 Kras/胰腺炎诱发的癌变中的作用，并建立使用 ω-3 多不饱和脂肪酸（PUFA）和小分子 sEH 预防胰腺癌的有效策略 抑制剂。 ω-3 PUFA 的抗炎/致癌作用是众所周知的；但其机制仍不清楚。在三种主要代谢途径（COX、LOX 和 CYP）中，ω-3 PUFA 主要由 CYP 环氧化酶代谢，导致 ω-3 环氧脂肪酸（ω-3 环氧化物）的积累；和 ω-3 PUFA 是 COX 和 LOX 的不良底物。 Fat1 转基因小鼠在所有器官中将 ω-6 转化为 ω-3 PUFA。补充 ω-3 PUFA 的人类和 Fat1 小鼠的脂质代谢组学分析进一步证明 ω-3 环氧化物是主要代谢物。功能研究表明，ω-3 环氧化物是高效代谢物，可能通过靶向炎症信号和 MAP 激酶来发挥抗炎/致癌作用。然而，在生理条件下，这些 ω-3 环氧化物很快就会被二醇产物的 sEH 失活，并且 sEH 抑制剂似乎对于稳定/增强这些 ω-3 环氧化物的作用至关重要。因此，我们假设 ω-3 环氧化物是 ω-3 PUFA 的关键代谢物，通过靶向 Kras 激活的 MAP 激酶和炎症信号（NF-kB 和 PPARγ）来抑制炎症和癌变，并且 sEH 抑制是增强这些 ω-3 环氧化物对抗胰腺炎诱导的癌变作用的有效方法。有三个具体目标来检验我们的假设：1) 确定 Fat1 转基因、sEH 基因缺陷或其组合在稳定和增强 ω-3 环氧化物对 PanKras 小鼠中突变 Kras/胰腺炎诱导的致癌作用中的作用，2) 确定 ω-3 PUFA 与高效 sEH 抑制剂联合作为有效化学预防方法的有效性 3) 使用我们独特的细胞模型和分子生物学方法，测试我们的假设，即 ω-3 环氧化物是 ω-3 PUFA 的关键代谢物，通过靶向突变的 Kras 激活信号、炎症信号（NF-kB 和 PPARγ）和血管生成来抑制胰腺癌。