Define the role of REV-ERB in colonic RORgt+ regulatory T cells

定义 REV-ERB 在结肠 RORgt 调节性 T 细胞中的作用

基本信息

批准号：
10753360
负责人：
Ye Zheng
金额：
$ 28.5万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753360
关键词：
Agonist Antibodies Autoimmune Diseases Autoimmunity Binding Biological Assay CTLA4 gene Cell Lineage Cell physiology Cells Colitis Colon Colonic inflammation Data Development Equilibrium FOXP3 gene Family Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Homeostasis Human Immune system Immunosuppressive Agents Inflammation Inflammatory Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Interleukin-10 Knock-out Knockout Mice Lamina Propria Lead Link Lymphoproliferative Disorders Maintenance Maps Mediating Molecular Multiple Sclerosis Mus Nuclear Hormone Receptors Nuclear Receptors Orphan Outcome Outcome Study Play Population Predisposition Receptor Inhibition Regulatory T-Lymphocyte Repression Research Role Running Side Spleen T-Lymphocyte Testing Tissues Transcription Coactivator Transcription Factor 3 Transcription Repressor Tretinoin Work anti-tumor immune response conditional knockout experimental study genome-wide immunopathology in vivo in vivo Model insight loss of function mutation member mouse model murine colitis new therapeutic target next generation sequencing prevent protective effect receptor receptor function therapeutic development therapeutic target transcription factor transcriptome sequencing

Agonist Antibodies Autoimmune Diseases Autoimmunity Binding Biological Assay CTLA4 gene Cell Lineage Cell physiology Cells Colitis Colon Colonic inflammation Data Development Equilibrium FOXP3 gene Family Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Homeostasis Human Immune system Immunosuppressive Agents Inflammation Inflammatory Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Interleukin-10 Knock-out Knockout Mice Lamina Propria Lead Link Lymphoproliferative Disorders Maintenance Maps Mediating Molecular Multiple Sclerosis Mus Nuclear Hormone Receptors Nuclear Receptors Orphan Outcome Outcome Study Play Population Predisposition Receptor Inhibition Regulatory T-Lymphocyte Repression Research Role Running Side Spleen T-Lymphocyte Testing Tissues Transcription Coactivator Transcription Factor 3 Transcription Repressor Tretinoin Work anti-tumor immune response conditional knockout experimental study genome-wide immunopathology in vivo in vivo Model insight loss of function mutation member mouse model murine colitis new therapeutic target next generation sequencing prevent protective effect receptor receptor function therapeutic development therapeutic target transcription factor transcriptome sequencing

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项目摘要

PROJECT SUMMARY Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing autoimmune disease. Defective Treg function leads to autoimmune diseases, while intra-tumor Tregs can block effective anti-tumor immune responses. Tregs can undergo further specialization in adaptation to their tissue microenvironment. Recent studies showed that a unique RORgt (retinoic acid–related orphan receptor gamma t) expressing Treg cell population could be induced in the colon lamina propria. These RORgt+ Tregs play an important role in the suppression of colon inflammation. In Treg cells, REV-ERBa is highly expressed in RORgt+ colonic Tregs, but not in RORgt- colonic Tregs or spleen Tregs. Mice with Treg-specific deletion of REV-ERB were more susceptible to TNBS-induced colitis with decreased RORgt+ Treg cells and increased Th1/Th17 cell- mediated inflammation in the colon. RNA-sequencing experiment showed that the expression of a set of genes related to Treg function, including CTLA-4, IL-10, and c-Maf, were reduced in REV-ERB deficient colonic Tregs compared to WT controls. To study the mechanism of gene regulation by REV-ERB in Tregs, Dr. Zheng’s lab performed Cut & Run assays with WT RORgt+ iTregs using Foxp3, REV-ERBa, and RORgt antibodies to map their binding peaks genome-wide. The results showed a significant overlap of the binding peaks of these 3 transcription factors, suggesting coordination in gene regulation among Foxp3, REV-ERB, and RORgt in Treg cells. The overall objective of the proposed study is to define the role of REV-ERB in Treg function. This goal will be accomplished by dissecting the molecular mechanism of REV-ERB function in RORgt+ Treg cells (Aim 1), and characterizing the role of REV-ERB in Treg in mouse models of IBD (Aim 2). The outcomes of the proposed study are expected to reveal the functional and mechanistic role of REV-ERB in RORgt+ Tregs. Such results are expected to further advance our understanding of how the identity and function of RORgt+ Tregs are established and maintained. Additionally, this study will provide key insights into how transcriptional repressor such as REV- ERB serves as key regulator and tune the function of transcriptional activators in Treg cells. Finally, the outcomes of this study could provide evidence supporting the development of therapeutics targeting REV-ERB for IBD treatment.

项目摘要调节性T细胞（TREG）在保持免疫系统平衡并防止免疫系统方面起着至关重要的作用自身免疫性疾病。 Treg功能有缺陷导致自身免疫性疾病，而肿瘤内Treg可以阻止有效的抗肿瘤免疫反应。 Tregs可以进一步专业地适应其组织微环境。最近的研究表明，独特的Rorgt（视黄酸相关的孤儿受体伽玛 t）可以在结肠椎板上诱导表达Treg细胞种群。这些Rorgt+ Tregs播放在抑制结肠注射中的重要作用。在Treg细胞中，Rev-Erba在Rorgt+中高度表达结肠treg，但不在rorgt-colonic tregs或脾脏中。 treg特定删除Rev-erb的小鼠更容易受到TNBS诱导的结肠炎的影响，而Rorgt+ Treg细胞降低，并增加了Th1/Th17细胞结肠介导的炎症。 RNA测序实验表明一组基因的表达在Rev-ERB缺陷的结肠Treg中，与Treg功能有关，包括CTLA-4，IL-10和C-MAF 与WT对照相比。为了研究tregs Rev-erb基因调节的机制，Zheng博士的实验室使用foxp3，rev-erba和rorgt抗体进行剪切的cut＆运行测定它们的结合峰全基因组。结果表明，这3的结合峰有显着的重叠转录因子，表明Treg中FOXP3，Rev-ERB和RORGT之间的基因调节协调细胞。拟议的研究的总体目的是定义Rev-erb在Treg功能中的作用。这个目标将可以通过解剖Rorgt+ Treg细胞中Rev-ERB功能的分子机制来完成（AIM 1），并表征Rev-erb在Treg在IBD小鼠模型中的作用（AIM 2）。提议的结果预计研究将揭示Rev-ERB在RORGT+ Tregs中的功能和机械作用。这样的结果是期望进一步促进我们对如何建立Rorgt+ Treg的身份和功能的理解并保持。此外，这项研究将提供有关转录复制品（例如Rev-）的关键见解。 ERB充当关键调节剂，并调整Treg细胞中转录激活剂的功能。最后，结果这项研究可以提供支持针对IBD Rev-ERB的治疗剂开发的证据治疗。