Mechanistic studies of Interleukin 10 gene regulation in intestinal CD4 T cells

肠道CD4 T细胞白细胞介素10基因调控机制研究

• 批准号: 8741733
• 负责人: Carson E Moseley
• 金额: $ 3.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-10 至 2017-06-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741733
• 关键词: Ablation; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Sites; Bioinformatics; CD4 Positive T Lymphocytes; Colitis; Communication; Complex; Crohn' s disease; Data; Development; Disease; Disease model; Enteral; Environment; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Growth Factor; Homeostasis; Human; IL10 gene; Immune; Immune response; Immunology; In Vitro; Incidence; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intestines; Kinetics; Knockout Mice; Learning; Light; Maps; Mediating; Messenger RNA; Modeling; Molecular; Mus; Mutation; North America; Pathogenesis; Patients; Physicians; Production; Reagent; Regulation; Repression; Research; Role; Scientist; Signal Transduction; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Training; Training Programs; Transcription Repressor/Corepressor; Ulcerative Colitis; Work; Zinc Fingers; burden of illness; career; cell type; cytokine; design; early onset; experience; genome wide association study; human disease; in vivo; in vivo Model; insight; interleukin-10 receptor; mouse model; new therapeutic target; novel therapeutics; prevent; protein expression; public health relevance; research study; success; transcription factor

DESCRIPTION (provided by applicant): Inflammatory Bowel Diseases (IBD), including Crohn's Disease and Ulcerative Colitis, result from complex interactions between host and environment leading to an excessive inflammatory response to the intestinal microbiota. Although several immunomodulatory therapies exist, many patients still experience a severe burden of disease. Due to the fact that the incidence of IBD is increasing both in North America and abroad, new therapeutic avenues are needed to more successfully treat these disorders. Interleukin-10 is a dimeric cytokine with potent anti-inflammatory functions in vivo. This is especially true in the intestinal tract, where IL-10 is essential to prevent excessive enteric inflammation in both mice and humans. However, modulating IL-10 production clinically has been hampered by a lack of understanding of the complexity of IL10 gene regulation. Here, we provide preliminary evidence that the transcriptional repressor Gfi1 acts to repress Il10 transcription in multiple lineages of CD4+ T cells. Furthermore, we show that Gfi1 deficient T cells do not drive severe disease in the CD45RBhi transfer model of colitis. Building on this preliminary work, we first propose to determine the mechanism of Gfi1 regulation of Il10 in CD4+ T cell subsets using a combined approach of gene and protein expression analysis, bioinformatics, and ChIP studies. Secondly, we will identify if the effect on Il10 is the protectiv mechanism in mouse models of IBD, and which T cell subsets contribute to this protection. The training program, sponsored by Dr. Casey Weaver, will allow for the learning of a variety of techniques in immunology, genetics, and IBD-directed research. Additionally, it will allow for scientific project design, communication, and training that will be beneficial for a career as a physician-scientist. While this project will investigate the regulation of Il10 by the use of mous models, our molecular studies will be guided by data from GWAS of humans with IBD. Thus, it should also shed light on IL10 regulation in human disease.

描述（由申请人提供）：炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，是由宿主与环境之间复杂的相互作用导致肠道微生物群过度炎症反应所致。尽管存在多种免疫调节疗法，但许多患者仍然承受着严重的疾病负担。由于 IBD 的发病率在北美和国外都在增加，因此需要新的治疗途径来更成功地治疗这些疾病。 Interleukin-10 是一种二聚体细胞因子，在体内具有有效的抗炎功能。在肠道中尤其如此，IL-10 对于预防小鼠和人类过度肠道炎症至关重要。然而，由于缺乏对 IL-10 基因调控复杂性的了解，临床上调节 IL-10 的产生受到阻碍。在这里，我们提供了初步证据，证明转录抑制因子 Gfi1 在 CD4+ T 细胞的多个谱系中发挥抑制 Il10 转录的作用。此外，我们发现 Gfi1 缺陷 T 细胞不会在 CD45RBhi 结肠炎转移模型中导致严重疾病。 基于这项初步工作，我们首先建议使用基因和蛋白质表达分析、生物信息学和 ChIP 研究的组合方法来确定 CD4+ T 细胞亚群中 Gfi1 对 Il10 的调节机制。其次，我们将确定对 Il10 的影响是否是 IBD 小鼠模型中的保护机制，以及哪些 T 细胞亚群有助于这种保护。 该培训计划由 Casey Weaver 博士赞助，将允许学习免疫学、遗传学和 IBD 导向研究领域的各种技术。此外，它将允许进行科学项目设计、沟通和培训，这将有利于医生科学家的职业生涯。 虽然该项目将通过使用小鼠模型来研究 Il10 的调节，但我们的分子研究将以来自 IBD 人类 GWAS 的数据为指导。因此，它还应该揭示人类疾病中 IL10 的调节。