Inflammatory cascades disrupt Treg function through epigenetic mechanisms

炎症级联反应通过表观遗传机制破坏 Treg 功能

• 批准号: 9720045
• 负责人: William A Faubion
• 金额: $ 4.18万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9720045
• 关键词: Affect; Area; Autologous; Biological; Biology; Caring; Cell Therapy; Cell physiology; Cells; Chromatin; Chronic; Clinic; Clinical Trials; Complex; Cost Measures; Data; Disease; Disease remission; EZH2 gene; Economic Burden; Environment; Epigenetic Process; FOXP3 gene; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Grant; Homeostasis; Human; IL6 gene; Immune; Immune System Diseases; Immunology; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Inherited; Interleukin-1 beta; Intestines; Investigation; Investigational Therapies; Knock-out; Knowledge; Laboratories; Lead; Lymphocyte; Mediating; Mutation; Parents; Pathway interactions; Patients; Phosphorylation; Phosphorylation Inhibition; Play; Post-Translational Protein Processing; Prevalence; Process; Public Health; Publishing; Regulation; Regulatory T-Lymphocyte; Repression; Research; Role; Signal Pathway; Signal Transduction; Stem cells; Stimulus; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapy trial; Work; base; design; epigenetic regulation; epigenomics; experience; histone methyltransferase; immunoregulation; in vivo; inflammatory milieu; innovation; insight; loss of function; novel therapeutics; public health relevance; transcription factor

DESCRIPTION (provided by applicant): The transcription factor FOXP3 is critical to the regulation of numerous debilitating human immune-mediated diseases. Very recently, the essential role for the histone methyltransferase (HMT) EZH2 in the epigenetic regulation and function of FOXP3 has been described. Inflammatory pathways modify EZH2 activity, and inflammatory signaling impairs Treg function in vivo and in vitro. The biological impact of the FOXP3-EZH2 pathway to IBD is unknown. Our long-term goal is to dissect epigenetic mechanisms regulating Treg cellular differentiation and function, particularly within the setting o GI inflammatory diseases. These discoveries will facilitate design of human cell therapy trials for IBD. The objective of this grant is to characterize the role for EZH2 in Treg suppressive function. The central hypothesis is that EZH2 plays a critical role in the homeostasis of Treg cells, and the disruption of EZH2 function by inflammatory signaling pathways contributes to IBD. Our rationale is that identification of the mechanism(s) to restore Treg suppressive function in the setting of intestinal inflammation will offer new therapeutic opportunities. Our specific aims will test the following hypotheses: (Aim1) Repression of immunoregulatory gene networks by FOXP3 requires the formation of a complex between this transcription factor and EZH2; (Aim 2) Inflammatory stimuli, such as IL6 lead to EZH2 phosphorylation and thereby disrupt the enzymatic activity of this epigenomic regulator; (Aim 3) Inhibition of the IL6 to EZH2 signaling pathway permits sustained Treg suppressive function in the setting of intestinal inflammation. Upon conclusion, we will understand the role for EZH2 in Treg loss of function in the setting of active inflammation. This contribution is significant since it will establish that several pathways targeted by available therapies (ie IL1β, IL6, TNFα) have the potential to regulate EZH2 HMT activity through post- translational modifications. Furthermore, current Treg cell therapy trials, while promising have not addressed the key issue of in vivo inflammation-induced disruption of Treg function. The proposed research is innovative because we investigate the effect of inflammatory signaling pathways on epigenetic complexes in Treg cells, a heretofore-unexamined process. Insight into epigenetic mechanisms is impactful as T cell progenitor cells inherit the parent transcriptional profile and unlike genetic change, they are modifiable by currently available therapy.

描述(由申请人提供)：转录因子FOXP3对调节许多衰弱的人类免疫介导性疾病至关重要。最近，组蛋白甲基转移酶(HMT)EZH2在FOXP3的表观遗传调控和功能中的重要作用已被描述。炎症途径改变了EZH2的活性，而炎症信号在体内和体外都损害了Treg的功能。FOXP3-EZH2通路对IBD的生物学影响尚不清楚。我们的长期目标是剖析调节Treg细胞分化和功能的表观遗传学机制，特别是在胃肠道炎症性疾病的背景下。这些发现将有助于设计治疗IBD的人类细胞疗法试验。这项资助的目的是描述EZH2在Treg抑制功能中的作用。 中心假说是EZH2在Treg细胞的动态平衡中起关键作用，炎症信号通路破坏EZH2的功能有助于IBD的发生。我们的理论基础是，确定(S)在肠道炎症背景下恢复Treg抑制功能的机制将提供新的治疗机会。我们的特定目标将检验以下假设：(Aim1)FOXP3抑制免疫调节基因网络需要该转录因子与EZH2之间形成复合体；(Aim2)炎症刺激，如IL6导致EZH2磷酸化，从而破坏这个表观基因组调节因子的酶活性；(Aim3)抑制IL6到EZH2的信号通路允许在肠道炎症背景下持续的Treg抑制功能。在结论中，我们将了解EZH2在活动性炎症环境中Treg功能丧失中的作用。这一贡献意义重大，因为它将确立现有治疗靶向的几条途径(即IL1β、IL6、肿瘤坏死因子α)有可能通过翻译后修饰来调节EZH2HMT的活性。此外，目前的Treg细胞治疗试验虽然很有希望，但还没有解决体内炎症诱导的Treg功能中断这一关键问题。这项拟议的研究具有创新性，因为我们研究了炎症信号通路对Treg细胞表观遗传复合体的影响，这是一个迄今未被研究的过程。深入了解表观遗传机制是有影响的，因为T细胞前体细胞继承了父母的转录图谱，而且与遗传变化不同，它们可以通过目前可用的治疗方法进行修改。