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How does polyunsaturated fatty acid biosynthesis regulate T lymphocyte function?

多不饱和脂肪酸生物合成如何调节T淋巴细胞功能？

基本信息

批准号：
BB/S00548X/1
负责人：
Graham Burdge
金额：
$ 64.97万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS00548X%2F1
关键词：
How does polyunsaturated fatty acid

项目摘要

Polyunsaturated fatty acids (PUFA), also known as Omega-3 and Omega-6 fats, are important for the normal function of immune cells. When immune cells are activated by viruses or bacteria, they use PUFA to make chemical signals that control the immune response. However, older individuals are less able to fight infection or respond to vaccines, and are more likely develop inflammatory disease than their younger counterparts. The processes responsible for this decline in immune function are not understood fully. Therefore, it is important to understand how immune cells obtain PUFA to make the chemical signals that control the immune response and how this is affected by increasing age. Immune cells can obtain PUFA from blood. However, a small number of studies have suggested immune cells may be able to make PUFA from essential fatty acids (EFAs) that are derived from plants and have to be consumed in the diet. We have recently published the findings of a project funded by the BBSRC that investigated the ability of human immune cells to make PUFA from EFAs. We found that the biochemical processes that convert EPAs to PUFA are switched on when immune cells are simulated in culture, a process that mimics the immune response. Our results showed that this involves changes in the control of a group of genes that contain the information to make the enzymes that convert EFAs to PUFA. This change in gene activity involved adaptation of a major gene control process; DNA methylation. We also found that blocking an enzyme involved in PUFA synthesis stopped immune cells proliferating, a critical early stage in the immune response. These results are important because they show for the first time that PUFA synthesis regulates the immune response. The aim of this project is to investigate the processes that link the activation of PUFA synthesis in immune cells to their ability to multiply. We will study T cells, a type of immune cell with a wide range of functions, from two groups of healthy human volunteers. First, we will use T cells from men and women aged 18 to 30 years to carry out detailed characterisation of PUFA synthesis by decreasing, in turn, the activity of each of the genes involved. We will relate this to the ability of T cells to become activated and to proliferate over the time course of the immune response. We will investigate whether PUFA from the environment of the T cells or their ability to convert EPAs to PUFA is the most important source of PUFA for making for chemical signals that regulate the immune response. Two possible processes that could link PUFA synthesis to T cell proliferation will be investigated. Activated T cells form structures on their surface that facilitate the action of chemical signs that drive the immune response. These microdomains contain a specific type of PUFA; very long chain PUFA (VLCPUFA) that control their formation which are derived from PUFA of the type synthesised by activated T cells. We will test whether EFAs are converted to VLCPUFA in activated T cells and, if so, how this is controlled. We will investigate whether PUFA synthesised from EFAs are used to synthesise chemical signals that drive the immune response. We will also determine how DNA methylation controls the activation of genes involved in PUFA synthesis. Finally, T cells from a second group of older men and women (aged 65 to 75 years) will be studied to determine whether the processes that link PUFA synthesis to T cell activation change with increasing age.This area of research is very new, but it has potential to substantially change understanding of the way in which immune cells become activated to mount an immune response. Potential benefits of this knowledge are that it may allow the development of new ways to support optimal immune function, for example through nutrition, and to understand how the effectiveness of the immune response differs between individuals and with increasing age.

多不饱和脂肪酸(PUFA)，也被称为欧米茄-3和欧米茄-6脂肪，对免疫细胞的正常功能非常重要。当免疫细胞被病毒或细菌激活时，它们会使用多不饱和脂肪酸来产生控制免疫反应的化学信号。然而，与年轻人相比，老年人对抗感染或对疫苗的反应能力较差，更有可能患上炎症性疾病。免疫功能下降的原因尚不完全清楚。因此，重要的是要了解免疫细胞如何获得多不饱和脂肪酸，以产生控制免疫反应的化学信号，以及这是如何受到年龄的影响的。免疫细胞可以从血液中获得多不饱和脂肪酸。然而，少数研究表明，免疫细胞可能能够从从植物中提取的必需脂肪酸(EFA)中产生多不饱和脂肪酸，这些脂肪酸必须在饮食中摄入。我们最近发表了由BBSRC资助的一个项目的结果，该项目调查了人类免疫细胞从EFA中制造多不饱和脂肪酸的能力。我们发现，当免疫细胞在培养中被模拟时，将EPA转化为PUFA的生化过程被开启，这一过程模拟了免疫反应。我们的结果表明，这涉及到一组基因控制的变化，这些基因含有将EFA转化为PUFA的酶的信息。基因活性的这种变化涉及到一个主要的基因控制过程的适应，即DNA甲基化。我们还发现，阻断一种参与多不饱和脂肪酸合成的酶可以阻止免疫细胞的增殖，这是免疫反应的一个关键早期阶段。这些结果很重要，因为它们首次表明多不饱和脂肪酸的合成调节免疫反应。该项目的目的是研究免疫细胞中多不饱和脂肪酸合成的激活与其增殖能力之间的联系。我们将研究T细胞，这是一种具有广泛功能的免疫细胞，来自两组健康的人类志愿者。首先，我们将使用18岁至30岁的男性和女性的T细胞，通过依次降低涉及的每个基因的活性来详细描述多不饱和脂肪酸的合成。我们将把这与T细胞在免疫反应过程中被激活和增殖的能力联系起来。我们将研究T细胞环境中的多不饱和脂肪酸或其将EPA转化为多不饱和脂肪酸的能力是否是多不饱和脂肪酸最重要的来源，以形成调节免疫反应的化学信号。将研究两种可能的将多不饱和脂肪酸合成与T细胞增殖联系起来的过程。被激活的T细胞在其表面形成结构，促进驱动免疫反应的化学信号的行动。这些微域包含一种特定类型的多不饱和脂肪酸；控制其形成的超长链多不饱和脂肪酸(VLCPUFA)，其来源是由激活的T细胞合成的类型的多不饱和脂肪酸。我们将测试EFA是否在激活的T细胞中转化为VLCPUFA，如果是，这是如何控制的。我们将调查从EFA合成的多不饱和脂肪酸是否被用来合成驱动免疫反应的化学信号。我们还将确定DNA甲基化如何控制参与多不饱和脂肪酸合成的基因的激活。最后，将对第二组老年男性和女性(65岁至75岁)的T细胞进行研究，以确定将PUFA合成与T细胞激活联系起来的过程是否随着年龄的增长而变化。这一研究领域非常新，但它有可能显著改变对免疫细胞激活以启动免疫反应的方式的理解。这种知识的潜在好处是，它可能允许开发新的方法来支持最佳免疫功能，例如通过营养，并了解免疫反应的有效性如何在个体之间和随着年龄的增长而不同。