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（由适用提供）：转录因子FOXP3对于调节许多令人衰弱的人类免疫介导的疾病至关重要。最近，已经描述了组蛋白甲基转移酶（HMT）EZH2在FOXP3的表观遗传调节和功能中的重要作用。炎症途径改变了EZH2活性，炎症信号传导会损害体内和体外的Treg功能。 FOXP3-EZH2途径对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机制，尤其是在OGI炎症性疾病的情况下。这些发现将促进IBD人类细胞疗法试验的设计。该赠款的目的是表征EZH2在Treg抑制功能中的作用。 中心假设是EZH2在Treg细胞的稳态中起着至关重要的作用，并且炎症信号通路对EZH2功能的破坏有助于IBD。我们的理由是，在肠道炎症的情况下恢复Treg抑制功能的机制的鉴定将提供新的治疗机会。我们的具体目的将检验以下假设：（ AIM1）FOXP3对免疫调节基因网络的抑制需要在该转录因子和EZH2之间形成复合物； （AIM 2）炎症刺激，例如IL6导致EZH2磷酸化，从而破坏该表观遗传学调节剂的酶活性； （目标3）抑制IL6对EZH2信号通路允许在肠道注射的情况下持续treg抑制功能。总结一下，我们将了解EZH2在主动感染中的功能丧失中的作用。这种贡献很重要，因为它将确定可用疗法（IEL1β，IL6，TNFα）靶向的几种途径具有通过翻译后修饰来调节EZH2 HMT活性的潜力。此外，目前的Treg细胞疗法试验虽然没有解决体内炎症引起的Treg功能中断的关键问题。提出的研究具有创新性，因为我们研究了炎症信号传导途径对迄今为止未经证实的过程Treg细胞中表观遗传复合物的影响。对表观遗传机制的洞察力具有影响，因为T细胞祖细胞继承了母体转录谱，并且与遗传变化不同，它们可以通过当前可用的治疗进行修改。