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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

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.

项目总结