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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

基本信息

批准号：
9104693
负责人：
William A Faubion
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/9104693
关键词：
Address Affect Area Autologous Biological Biology Caring Cell Therapy Cell physiology Chromatin Chronic Clinic Clinical Trials Complex Cost Measures Data Disease Disease remission EZH2 gene Economic Burden Environment Epigenetic Process FOXP3 gene Gene Expression Regulation Gene Targeting Genes Goals Grant Homeostasis Human IL6 gene Immune Immune System Diseases Immunology In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Inherited Innovative Therapy Interleukin-1 beta Intestines Investigation Investigational Therapies Knock-out Knowledge Laboratories Lead Lymphocyte Mediating Modification Mutation Parents Pathway interactions Patients Phosphorylation Phosphorylation Inhibition Phosphotransferases Play Post-Translational Protein Processing Prevalence Process Public Health Publishing Qualifying Regulation Regulatory T-Lymphocyte Repression Research Resistance Role Signal Pathway Signal Transduction Stem cells Stimulus T-Lymphocyte TNF gene Testing Therapeutic Therapy trial Work base design epigenetic regulation epigenomics experience gene repression histone methyltransferase in vivo innovation insight loss of function novel therapeutics preclinical study public health relevance research study therapy design transcription factor

项目摘要

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.