Corepressors in regulatory T cell development and function

调节性 T 细胞发育和功能中的辅阻遏物

• 批准号: 10543410
• 负责人: Natalie Anne David
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-08 至 2024-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543410
• 关键词: ATAC-seq; Adult; Affect; Autoimmune Diseases; Autoimmunity; Bioinformatics; Biological Assay; Biology; CD28 gene; CD4 Positive T Lymphocytes; Cells; ChIP-seq; Childhood; Chromatin; Collagen Arthritis; Complex; DNA; DNA Binding; Data; Defect; Development; Disease; Epigenetic Process; Exhibits; FOXP3 gene; Flow Cytometry; Gene Expression; Gene Silencing; Generations; Genes; Genetic Enhancer Element; Genetic Transcription; Genomics; Histone Deacetylase; Histone Deacetylation; Homeostasis; IL2RA gene; Immune Tolerance; Immune response; Immune system; Impairment; In Vitro; Individual; Infection; Interleukin-2; MADH2 gene; MADH4 gene; Modeling; Modification; Morbidity - disease rate; Mouse Strains; Mus; NCOR1 gene; NCOR2 gene; Nuclear Receptors; Pathogenesis; Peripheral; Phenotype; Physicians; Population; Preparation; Process; Proteins; Regulatory T-Lymphocyte; Research; Rheumatology; Role; Sampling; Scientist; Signal Transduction; Site; Stat5 protein; T-Cell Development; Testing; Thymus Gland; Transforming Growth Factor beta; United States; Wild Type Mouse; Work; autoreactivity; computerized tools; defined contribution; epigenetic regulation; experience; genetic corepressor; human disease; human model; in vivo; insight; mortality; mouse model; novel therapeutics; peripheral lymphoid organ; prevent; progenitor; recruit; single-cell RNA sequencing; skills; therapy development; thymocyte; transcription factor

PROJECT ABSTRACT Regulatory T cells (Tregs) are critical in dampening the immune response following an infection and suppressing autoreactive cells. Defects in Tregs contribute to disease pathogenesis in some autoimmune conditions. While much is known about the roles of individual transcription factors in regulating Treg biology, the involvement of these transcription factors in the epigenetic regulation of Tregs remains largely unexplored. Treg-promoting transcription factors include FOXP3, STAT5, and SMAD2/3-SMAD4. These transcription factors promote Treg-specific gene expression and silence genes associated with other T helper subsets. The precise mechanism through which they positively and negatively regulate gene transcription remains unclear. Transcription factors can associate with corepressors, which then recruit histone deacetylases to the site of DNA binding. The resulting histone deacetylation decreases gene transcription. FOXP3, STAT5, and SMAD are all known to associate with corepressor proteins NCOR1 and NCOR2/SMRT. These interactions suggest a role for NCOR1/2 in regulating Tregs. Preliminary data obtained from NCOR1/2-deficient mice demonstrate a severe quantitative defect in all CD4 T cells, including Tregs. NCOR1/2-deficient mice also have impaired thymic Treg development and reduced differentiation into Tregs from naïve CD4 T cells. The effects of NCOR1/2 deletion on Tregs recapitulate the phenotype observed in STAT5-deficient mice. I hypothesize that the association of Treg-promoting transcription factors and NCOR1/2 promote normal Treg development and function through control of epigenetic modifications. My hypotheses will be tested by pursuing the following aims: (1) identifying the contribution of NCOR1/2 to Treg differentiation and function and (2) defining the contributions of transcription factor-NCOR1/2 complexes to the epigenetic landscape of Tregs. Completion of these studies will reveal important information about the role of epigenetic modifications in Treg differentiation and homeostasis. It will also provide insight into developing therapies to enhance Treg quantity and function and restore immunological tolerance in autoimmune diseases.

项目摘要 调节性T细胞（TCFs）在抑制感染后的免疫反应方面至关重要， 抑制自身反应细胞在某些自身免疫性疾病中，TdR的缺陷有助于疾病的发病机制。 条件虽然对单个转录因子在调节Treg生物学中的作用了解很多， 这些转录因子参与TGFAP的表观遗传调节在很大程度上仍未被探索。 Treg促进转录因子包括FOXP 3、STAT 5和SMAD 2/3-SMAD 4。这些转录 因子促进Treg特异性基因表达，并沉默与其他辅助性T细胞亚群相关的基因。的 它们正、负调节基因转录的确切机制尚不清楚。 转录因子可以与辅阻遏物结合，辅阻遏物然后将组蛋白去乙酰化酶募集到转录位点。 DNA结合。由此产生的组蛋白去乙酰化降低基因转录。FOXP 3、STAT 5和SMAD 都已知与辅阻遏蛋白NCOR 1和NCOR 2/SMRT相关。这些相互作用表明， NCOR 1/2在调节THP中的作用。从NCOR 1/2缺陷小鼠获得的初步数据表明， 所有CD 4 T细胞（包括T细胞）严重数量缺陷。NCOR 1/2缺陷小鼠也有受损的 胸腺Treg发育和从幼稚CD 4 T细胞分化为T细胞的减少。的影响 TcR上的NCOR 1/2缺失重现了在STAT 5缺陷小鼠中观察到的表型。我假设 Treg启动子转录因子与NCOR 1/2启动子正常Treg相关性研究 通过控制表观遗传修饰的发育和功能。我的假设将由 （1）鉴定NCOR 1/2对Treg分化和功能的贡献， (2)定义转录因子-NCOR 1/2复合物对THBE表观遗传景观的贡献。 这些研究的完成将揭示关于表观遗传修饰在Treg中的作用的重要信息。 分化和稳态。它还将为开发增强Treg数量的疗法提供见解 并在自身免疫性疾病中发挥作用和恢复免疫耐受。