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

基本信息

批准号：
10459794
负责人：
Bing Li
金额：
$ 27.82万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/10459794
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 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

项目摘要

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.

项目概要/摘要尽管治疗方法取得了进步，但 2019 年美国仍有超过 600,000 人死于癌症。预防癌症消除了癌症发展过程中可能发生的死亡和/或发病的风险。预防被认为是应对癌症挑战的最有效方法。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 VITAL 试验并未显示这些补充剂的有益效果反映了人们对如何使用补充剂的机械知识差距。饮食因素调节健康。此更新应用程序的目标是确定细胞和健康。上皮脂肪酸结合蛋白（E-FABP）促进n-3脂肪酸的分子机制通过增强免疫细胞分化和抗肿瘤活性来介导肿瘤预防。上一个资助周期已成功将 E-FABP 确立为一种新的宿主源性癌症预防因子在我们的研究中，我们观察到不同类型的高脂肪饮食（HFD，45% 脂肪），包括可可脂（富含饱和脂肪酸，FA）、红花油（富含18:2亚油酸）、鱼油（富含 n-3 FA），均在小鼠模型中诱导相似程度的肥胖，然而，这些肥胖小鼠中的肿瘤生长。可可脂组增长最快，鱼油组增长最慢，差异显着。通过分析这些肥胖小鼠的免疫表型，我们发现了非典型的 CD8+ γδ T 细胞群体更有趣的是，鱼油饮食诱导的 CD8+ γδ T 明显上调。缺乏 E-FABP 的小鼠的分化和抗肿瘤作用减弱，这表明存在一种新的分子 E-FABP 介导的机制因此，我们发现 E-FABP 的宿主表达起着关键作用。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。解决本更新申请中的中心假设，具体目标 1 将通过以下方式确定机制。 E-FABP 促进 n-3 FA 诱导的免疫细胞分化。饮食 n-3 FA 的消耗通过 E- 调节 CD8+ γδ T 细胞分化的分子机制 FABP 依赖性表观遗传重编程特定目标 2 将描述 E-FABP 如何介导 n-3 FA- 目标 2 的结果有望揭示 E-FABP 促进宿主抗肿瘤活性。具体目标 3 将评估通过靶向免疫细胞和肿瘤来源的上皮细胞的活性。以优化的 n-3 FA 饮食为目标的 E-FABP 是否能有效预防肿瘤。该提案的成功完成将使E-FABP成为新的癌症预防目标，并具有对健康饮食介导的癌症预防具有重要的机制和临床意义。