E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function

E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防

• 批准号: 10320058
• 负责人: Bing Li
• 金额: $ 34.07万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320058
• 关键词: Address; Animals; Basic Science; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Clinical; Clinical Trials; Consumption; Custom; DNA; DNA methyltransferase inhibition; Data; Development; Diet; Dietary Factors; Dietary Fatty Acid; Epigenetic Process; Epithelial; Epithelial Cells; Exhibits; Fish Oils; Funding; Growth; Health; High Fat Diet; Human; Immune; Immunity; Immunologic Surveillance; Immunophenotyping; In Vitro; Interferons; Knockout Mice; Knowledge; Life Style; Linoleic Acids; Malignant Neoplasms; Mediating; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; Non obese; Obese Mice; Obesity; Oleic Acids; Olive oil preparation; Omega-3 Fatty Acids; Persons; Play; Population; Prevention; Production; Reactive Oxygen Species; Role; STAT3 gene; Safflower Oil; Saturated Fatty Acids; Signal Transduction; T cell differentiation; T-Lymphocyte; Therapeutic; Toxic effect; Tumor-Derived; Tumor-infiltrating immune cells; Vitamin D; Vitamins; World Health Organization; aldehyde dehydrogenase 1; antitumor effect; cancer prevention; cancer risk; cancer therapy; cocoa butter; conditional knockout; demethylation; design; dietary; dietary supplements; dosage; experimental study; fatty acid-binding proteins; good diet; improved; in vivo; insight; mortality risk; mouse model; neoplastic cell; novel; preclinical study; prevent; protein expression; response; sensor; tumor; tumor growth; γδ T cells

PROJECT SUMMARY/ABSTRACT Despite therapeutic advances, over 600,000 people in the US will die from cancer in 2019. Preventing cancer eliminates the risk of mortality and/or morbidity that may occur with the development of cancer. Thus, cancer prevention represents the most effective way for addressing cancer challenges. Healthy diet is considered be essential to reduce cancer risk by maintaining and improving immunity, but recent VITAL trials did not show beneficial effects of these supplements. The negative results reflect the mechanistic knowledge gap of how dietary factors modulate health. The objectives of this renewal application are to determine cellular and molecular mechanisms by which epithelial fatty acid binding protein (E-FABP) promotes n-3 fatty acid- mediated tumor prevention by enhancing immune cell differentiation and anti-tumor activity. Data collected in the last funding cycle have successfully established E-FABP as a new host-derived cancer prevention factor in non-obese subjects. During our studies, we observed that different types of high fat diets (HFD, 45% fat), including cocoa butter (rich in saturated fatty acids, FAs), safflower oil (rich in 18:2 linoleic acid), fish oil (rich in n-3 FAs), all induced similar degree of obesity in mouse models. However, tumor growth in these obese mice was dramatically different with the fastest growth in cocoa butter group and slowest in the fish oil group. In analyzing the immunophenotype of these obese mice, we found an atypical population of CD8+ γδ T cells that was specifically upregulated in the fish oil group. More interestingly, fish oil diet-induced CD8+ γδ T differentiation and anti-tumor effects were blunted in mice lacking E-FABP, suggesting a novel molecular mechanism mediated by E-FABP. Thus, we hypothesized that host expression of E-FABP plays a critical role in n-3 FA-induced immune cell differentiation and anti-tumor function. Three specific aims are proposed to address the central hypothesis in this renewal application. Specific Aim 1 will determine the mechanisms by which E-FABP promotes n-3 FA-induced immune cell differentiation. Experiments are designed to elucidate molecular mechanisms by which consumption of dietary n-3 FAs regulate CD8+ γδ T cell differentiation via E- FABP-dependent epigenetic reprogramming. Specific Aim 2 will delineate how E-FABP mediates n-3 FA- induced anti-tumor activity. Results of Aim 2 are expected to reveal that E-FABP promotes host anti-tumor activity through targeting both immune cells and tumor-derived epithelial cells. Specific Aim 3 will evaluate whether targeting E-FABP with optimized n-3 FA diets results in effective tumor prevention. In summary, successful completion of this proposal will offer E-FABP as a new cancer prevention target and have significant mechanistic and clinical implications for healthy diet-mediated cancer prevention.

项目摘要/摘要 尽管有治疗性进步，但2019年，美国有超过60万人死于癌症。预防癌症 消除了癌症发展可能发生的死亡率和/或发病率的风险。那，癌症 预防是应对癌症挑战的最有效方法。健康饮食被认为是 通过维持和提高免疫力来降低癌症风险至关重要，但最近的重要试验并未显示 这些补充剂的有益影响。负面的结果反映了方式的机理知识差距 饮食因素调节健康。此更新应用的目标是确定细胞和 上皮脂肪酸结合蛋白（E-FABP）促进N-3脂肪酸 - 通过增强免疫细胞分化和抗肿瘤活性，预防肿瘤。收集的数据 最后的融资周期已成功地建立了电子商务作为新的宿主衍生的癌症预防因素 非肥胖受试者。在我们的研究中，我们观察到不同类型的高脂饮食（HFD，45％脂肪）， 包括可可脂（富含饱和脂肪酸，FAS），红花油（富含18：2亚油酸），鱼油（富含鱼油） N-3 FAS），均在小鼠模型中诱导相似程度的肥胖。但是，这些肥胖小鼠的肿瘤生长 可可黄油群的生长最快，鱼油组的生长最快。在 分析这些肥胖小鼠的免疫表型，我们发现CD8+γδT细胞的非典型群体， 在鱼油组中专门更新。更有趣的是，鱼油饮食诱导的CD8+γδT 缺乏E-FABP的小鼠中分化和抗肿瘤作用被钝化，这表明一种新颖的分子 E-FABP介导的机制。这是我们假设宿主的E-FABP表达起着至关重要的作用 在N-3 FA诱导的免疫细胞分化和抗肿瘤功能中。提出了三个具体目标 解决此更新应用中的中心假设。具体目标1将通过 E-FABP促进了N-3 FA诱导的免疫细胞分化。实验旨在阐明 饮食N-3 Fas消耗的分子机制通过E-调节CD8+γδT细胞分化 依赖FabP的表观遗传重编程。特定的目标2将描述电子-FABP如何介导N-3 FA- 诱导的抗肿瘤活性。 AIM 2的结果有望揭示E-FABP促进宿主抗肿瘤 通过靶向免疫细胞和肿瘤衍生的上皮细胞的活性。特定目标3将评估 用优化的N-3 FA饮食靶向电子-FABP是否会导致有效的肿瘤预防。总之， 该提案的成功完成将为电子癌症提供作为新的预防癌症的目标，并具有 对健康饮食介导的癌症预防的重要机械和临床意义。