How beta-catenin expands Foxp3+RORgammat+ Pro-inflammatory T-regulatory cells

β-连环蛋白如何扩增 Foxp3 RORgammat 促炎性 T 调节细胞

• 批准号: 8761153
• 负责人: Fotini Gounari
• 金额: $ 41.41万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761153
• 关键词: Ablation; Acetylation; Acetyltransferase; Address; Attenuated; Binding Sites; Cancer Patient; Cells; Chromatin; Clinical; Colitis; Colon Carcinoma; Colonic Neoplasms; DNA; DNA Binding; Data; Development; EP300 gene; Epigenetic Process; Face; Favorable Clinical Outcome; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Genome; Health; Hematopoietic; Histone Acetylation; Histones; Human; Immunologic Surveillance; Immunotherapy; Inflammation; Inflammatory; Intervention; Intestines; Lead; Link; Lymphoid; Malignant Neoplasms; Measures; Molecular Profiling; Mus; Neoplasms; Outcome; Pathology; Pathway interactions; Polyps; Property; Proteins; Recruitment Activity; Regulatory T-Lymphocyte; Role; Signal Transduction; Site; T-Lymphocyte; Testing; Thymus Gland; Transferase; Work; base; beta catenin; cancer therapy; genome-wide; immune function; inhibitor/antagonist; mouse model; polyposis; programs; public health relevance; response; therapeutic target; thymocyte; tool; transcription factor; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Our preliminary work has established that regulatory T-cells (Tregs) have two faces in the pathology of colon cancer: one that suppresses inflammation and is protective, and another that is pro-inflammatory and tumor promoting. Preferential expansion of a pro-inflammatory subset of Tregs promotes oncogenesis and intestinal pathology. Pro-inflammatory Tregs are distinct from classical Tregs because they have activated ¿-catenin and express ROR?t, the signature transcription factor of TH17 cells and a transcriptional target of ¿-catenin. We have shown that expression of ROR?t by pro-inflammatory Tregs is linked to the development of colitis and polyposis. We have also shown that pro-inflammatory Tregs can be generated through targeted activation of ¿-catenin in Tregs, and that this results in colitis and colon cancer. We have evidence to suggest that expression of ROR?t is facilitated through enhanced chromatin accessibility. Consistent with this finding, activation of ¿-catenin in thymocytes enhances chromatin accessibility near DNA sites bound by its partner Tcf-1, and facilitates the recruitment of lymphoid transcription factors to these sites These chromatin changes were associated with activation of a group of inflammation-associated genes (including ROR?t) that define pro-inflammatory Tregs. Based on these observations, we hypothesize that ¿-catenin activation in Tregs initiates a pro-inflammatory and tumor promoting program driven by changes in chromatin landscape and gene expression. To test this hypothesis, we will address the following postulates: 1) ¿-catenin orchestrates a pro-inflammatory program in Tregs by initiating epigenetic and gene expression changes, 2) ¿-catenin is required for the generation of pro-inflammatory Tregs, 3) the Wnt/¿-catenin/Tcf-1 pathway is a viable therapeutic target for the treatment of human colon cancer. Accumulation of Tregs in colonic tumors has been linked with both poor and favorable clinical outcomes. Elucidating the properties and mechanisms that distinguish pathological from protective Tregs will provide the tools to specifically target the harmful subsets in cancer therapy. Therefore, findings from the proposed studies could redefine our current understanding of Treg function and immune intervention in colon cancer. Furthermore the proposed studies will elucidate fundamental mechanisms of action of the Wnt/¿-catenin/Tcf-1 pathway.

描述（由申请人提供）：我们的初步工作已经确定，调节性T细胞（T细胞）在结肠癌的病理学中有两个方面：一个是抑制炎症和保护性的，另一个是促炎和促肿瘤的。促炎性亚群的优先扩增促进肿瘤发生和肠道病理学。促炎性T细胞因子与经典T细胞因子不同，因为它们激活了β-连环蛋白并表达ROR？t，TH 17细胞的标志性转录因子和β-连环蛋白的转录靶点。我们已经表明，表达的ROR？通过促炎性T细胞因子的检测与结肠炎和息肉病的发展有关。我们还表明，促炎性Tcl 3可以通过靶向激活Tcl 3中的β-连环蛋白产生，这会导致结肠炎和结肠癌。我们有证据表明，表达ROR？通过增强的染色质可及性来促进t。与这一发现相一致的是，胸腺细胞中的<$-catenin的激活增强了其伴侣Tcf-1结合的DNA位点附近的染色质可及性，并促进了淋巴转录因子向这些位点的募集。t）定义促炎性THP。基于这些观察结果，我们假设TcB中的β-连环蛋白激活启动了由染色质景观和基因表达变化驱动的促炎和肿瘤促进程序。为了验证这一假设，我们将提出以下假设：1）<$-连环蛋白通过引发表观遗传和基因表达变化来协调Tcf中的促炎程序，2）<$-连环蛋白是产生促炎性Tcf所必需的，3）Wnt/<$-连环蛋白/Tcf-1途径是治疗人结肠癌的可行治疗靶标。结肠肿瘤中TdR的积累与不良和良好的临床结果有关。阐明区分病理性和保护性T细胞的性质和机制将提供在癌症治疗中特异性靶向有害亚群的工具。因此，拟议研究的结果可以重新定义我们目前对结肠癌中Treg功能和免疫干预的理解。此外，拟议的研究将阐明Wnt/β-catenin/Tcf-1通路的基本作用机制。