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

 描述（由申请人提供）：本项目的目的是确定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/胰腺炎诱导的致癌作用中的作用，并建立使用ω-3多不饱和脂肪酸（PUFA）和小分子sEH抑制剂预防胰腺癌的有效策略。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（考克斯、LOX和LOX）中，ω-3 PUFA主要由ω-3环氧氧化酶代谢，导致ω-3环氧脂肪酸（ω-3环氧化物）的积累; ω-3 PUFA是考克斯和LOX的不良底物。Fat 1转基因小鼠在所有器官中组成性地将ω-6转化为ω-3 PUFA。补充ω-3 PUFA的人类和Fat 1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环氧化物是负责抗炎/致癌作用的高效代谢物，可能通过靶向炎症信号和MAP激酶。然而，在生理条件下，这些ω-3环氧化物被sEH快速灭活为二醇产物，并且sEH抑制剂似乎对稳定/增强这些ω-3环氧化物作用至关重要。因此，我们假设ω-3环氧化物是ω-3 PUFA通过靶向Kras激活的MAP激酶和炎症信号（NF-κ B和PPARγ）来抑制炎症和致癌的关键代谢物，并且sEH抑制是增强这些ω-3环氧化物对抗胰腺炎诱导的致癌作用的有效途径。有三个具体目标来检验我们的假设：1）确定Fat 1转基因、sEH基因缺陷或它们的组合在稳定和增强ω-3环氧化物对PanKras小鼠中突变型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抑制剂组合作为针对胰腺炎的有效化学预防方法的有效性-3）利用我们独特的细胞模型和分子生物学方法，验证ω-3环氧化物是ω-3 PUFA通过靶向突变型Kras激活信号、炎症信号（NF-κ B和PPARγ）和血管生成抑制胰腺癌的关键代谢产物的假设。

 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.