The role of Mediator in T-bet-dependent gene activation and its dysregulation in mucosal inflammatory disease.

介体在 T-bet 依赖性基因激活及其在粘膜炎症性疾病中的失调中的作用。

• 批准号: MR/R001413/1
• 负责人: Richard Jenner
• 金额: $ 69.68万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR001413%2F1
• 关键词: role; Mediator; bet; dependent; gene

Our immune system functions to protect us from infection and keep commensal microorganisms that live on and within our bodies in check. However, the immune system can also become dysregulated, instead damaging organs and tissues. This can cause chronic inflammatory diseases, which include Crohn's disease, ulcerative colitis and celiac disease, which primarily affect the bowel. These diseases cluster in families, suggesting a genetic component. Unfortunately, the number of people affected by these diseases is increasing and the treatment options that are currently available are poor. There are a number of components of the immune system. CD4 T cells secrete signals that help other cells control microorganism numbers. CD4 T cells are normally resting but when the cell detects a foreign object, the cell changes into one of a number of different types of effector cell, each of which activates a different component of the immune response. The type of effector cell it becomes depends on the type of foreign object detected and allows the immune response to tailor itself to different threats. It is also important that the appropriate balance between these different effector types is maintained because excessive activation can lead to inflammatory diseases.The differentiation of CD4 T cells into effector lineages is controlled by transcription factors, proteins that bind to specific sites on DNA and turn on and off near-by genes. Thus, if we could understand how these transcription factors function to turn on and off genes, and how this changes in disease, we might be able to develop drugs that modulate this process and block damaging immune responses.We have identified a set of proteins that are required by a transcription factor called T-bet to activate immune response genes. Blocking the activity of one of these proteins, Cdk9, reduced inflammation in a model of the inflammatory eye disease, uveitis. We have also found that genetic variants that are more often found in people with inflammatory bowel disease affect the ability of T-bet to bind to DNA. This suggests that these genetic variants increase disease risk because they obstruct how immune genes are normally turned on and off.The aim of this project is to determine how T-bet works with the proteins we have identified to turn immune genes on, to discover how the genetic variants associated with disease affect this process, and to test whether blocking the function of Cdk9 and other proteins in this pathway can reduce symptoms in models of inflammatory bowel disease.This work will increase our understanding of the normal process through which genes are turned on during an immune response, which will be important to support this process in people whose immune systems are not functioning well. This research will also reveal how the genetic variants present in some people cause dysregulation of the immune system and how this can increase the risk of those individuals developing inflammatory diseases. Finally, this work will identify a set of possible drug targets through which chronic inflammatory diseases might be treated in the future.

我们的免疫系统的功能是保护我们免受感染，并控制生活在我们身体上和体内的共生微生物。然而，免疫系统也可能变得失调，反而会损害器官和组织。这会导致慢性炎症性疾病，包括克罗恩病、溃疡性结肠炎和乳糜泻，这些疾病主要影响肠道。这些疾病在家族中聚集，表明存在遗传因素。不幸的是，受这些疾病影响的人数正在增加，目前可用的治疗方案很差。免疫系统有许多组成部分。CD4T细胞分泌信号，帮助其他细胞控制微生物数量。CD4T细胞通常处于休眠状态，但当细胞检测到异物时，细胞就会变成多种不同类型的效应细胞中的一种，每种效应细胞都会激活免疫反应的不同组成部分。它变成的效应细胞的类型取决于检测到的异物的类型，并允许免疫反应根据不同的威胁进行调整。同样重要的是，保持这些不同效应器类型之间的适当平衡，因为过度激活会导致炎症性疾病。CD4T细胞向效应器谱系的分化受转录因子控制，转录因子是一种蛋白质，与DNA上的特定位置结合，并开启和关闭邻近基因。因此，如果我们能够了解这些转录因子如何发挥作用来开启和关闭基因，以及这种功能在疾病中是如何变化的，我们就可能开发出调节这一过程并阻止破坏性免疫反应的药物。我们已经确定了一组被称为T-bet的转录因子激活免疫反应基因所需的蛋白质。阻断其中一种蛋白质CDK9的活性，可以减少炎症性眼病葡萄膜炎模型的炎症。我们还发现，炎症性肠病患者中更常见的基因变异会影响T-bet与DNA结合的能力。这表明这些基因变异会增加疾病风险，因为它们阻碍了免疫基因的正常开启和关闭。这个项目的目的是确定T-bet如何与我们识别的蛋白质一起开启免疫基因，发现与疾病相关的遗传变异如何影响这一过程，并测试阻断这一途径中的CDK9和其他蛋白质的功能是否可以减少炎症性肠病模型中的症状。这项工作将增加我们对免疫反应过程中基因被打开的正常过程的理解，这对于支持免疫系统功能不佳的人的这一过程将是重要的。这项研究还将揭示一些人中存在的基因变异如何导致免疫系统调节失调，以及这如何增加这些人患炎症性疾病的风险。最后，这项工作将确定一组可能的药物靶点，通过这些靶点，慢性炎症性疾病可能在未来得到治疗。

项目成果

The Th1 cell regulatory circuitry is largely conserved between human and mouse.

• DOI: 10.26508/lsa.202101075
• 发表时间: 2021-11
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Henderson S;Pullabhatla V;Hertweck A;de Rinaldis E;Herrero J;Lord GM;Jenner RG
• 通讯作者: Jenner RG

The Th1 cell regulatory circuitry is largely conserved between human and mouse

Th1 细胞调节电路在人类和小鼠之间很大程度上是保守的

• DOI: 10.1101/2021.01.11.426266
• 发表时间: 2021
• 作者: Henderson S

The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes.

• DOI: 10.1093/nar/gkac258
• 发表时间: 2022-05-06
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Hertweck, Arnulf;Vila de Mucha, Maria;Barber, Paul R.;Dagil, Robert;Porter, Hayley;Ramos, Andres;Lord, Graham M.;Jenner, Richard G.
• 通讯作者: Jenner, Richard G.

A Crohn's Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling.

克罗恩疾病相关的IL2RA增强子变体通过调节对IL-2信号的反应性来决定T细胞免疫的平衡。

• DOI: 10.1093/ecco-jcc/jjab103
• 发表时间: 2021-12-18
• 期刊: Journal of Crohn's & colitis
• 作者: Goldberg R;Clough JN;Roberts LB;Sanchez J;Kordasti S;Petrov N;Hertweck A;Lorenc A;Jackson I;Tasker S;Appios A;Omer O;Parkes M;Prescott N;Jenner RG;Irving PM;Lord GM
• 通讯作者: Lord GM

The Study of Protein-DNA Interactions in CD4+ T-Cells Using ChIPmentation.

使用 ChIPmentation 研究 CD4 T 细胞中的蛋白质-DNA 相互作用。

• DOI: 10.1007/978-1-0716-1311-5_17
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Hertweck A