Role of Blimp-1 in preventing chronic intestinal mucosal inflammation.

Blimp-1 在预防慢性肠粘膜炎症中的作用。

• 批准号: 8579614
• 负责人: Gislaine A Martins
• 金额: $ 39.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-29 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579614
• 关键词: Autoimmune Diseases; B lymphocyte-induced maturation protein 1; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cells; Chromatin; Chronic; Colitis; Colon; Complex; Development; Down-Regulation; Effector Cell; Environment; Eragrostis; Gene Expression; Gene Expression Profiling; Genes; Genetic Polymorphism; Genetic Programming; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Homing; Human; IL17 gene; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Interleukin-17; Intestinal Mucosa; Intestines; Lead; Link; Lymphocyte; Lymphoid Tissue; Maintenance; Mediating; Molecular; Mucositis; Mucous Membrane; Mus; PRDM1 gene; Phenotype; Play; Process; Production; Property; Reporter; Repression; Role; Site; Subfamily lentivirinae; Surface; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Organisms; cytokine; histone modification; in vivo; insight; novel therapeutic intervention; prevent; programs; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Maintenance of the intestinal mucosa homeostasis is achieved by complex mechanisms, including active downregulation of immune responses1, 2. Disruption of these mechanisms results in chronic immune responses towards the commensal flora which can lead to the development of Inflammatory Bowel Diseases (IBD), 3, 4 and may also contribute to autoimmune diseases at extra-intestinal sites5, 6. CD4+T helper effector (Teff) and regulatory (Treg) lymphocytes are important players in the maintenance of intestinal mucosa homeostasis2, but the molecular mechanisms underlying their function under homeostatic and inflammatory conditions at the intestinal mucosa are not fully understood. B-lymphocyte-induced maturation protein -1 (Blimp-1) is a transcription factor essential for normal development and immunity7. Blimp-1 is expressed in Teff and Treg cells11-15 and T-cell specific deletion of Blimp-1 in mice (Blimp-1CKO) results in development of severe intestinal inflammation11, associated with the accumulation of CD4+ T cells in the colon and aberrant production of inflammatory cytokines11, 16, 17. Polymorphisms in PRDM1 (encoding Blimp-1) are associated with severe inflammatory conditions in humans, including IBD18, 19. Thus, Blimp-1 appears to be a critical regulator of Teff cell terminal differentiation although the speciic transcriptional programs controlled by Blimp-1 in T cells remain largely unknown. The studies proposed here will test the hypothesis that Blimp-1 is required to repress the acquisition of an inflammatory phenotype by mucosal T cells and therefore plays a non redundant role in the maintenance of intestinal mucosa homeostasis. To test this hypothesis we will a) characterize Blimp-1-expressing T cells in the intestinal mucosa and determine the mechanisms regulating Blimp-1 expression; b) identify the mechanisms by which T cell-specific lack of Blimp-1 leads to chronic intestinal inflammation; and c) Determine the molecular mechanisms by which Blimp-1 prevents the acquisition of inflammatory phenotype. We anticipate that the completion of these studies will provide new insights into the genetic programs underlying the differentiation of inflammatory effector T cells, and implicate Blimp-1 as a key repressor of the processes leading to chronic conditions such as IBD.

描述（由申请人提供）：通过复杂机制来实现肠粘膜稳态的维持，包括对免疫反应的积极下调。 6。CD4+T辅助效应子（TEFF）和调节（TREG）淋巴细胞是维持肠粘膜稳态的重要参与者，但是在肠粘膜下稳态和炎症条件下功能下的分子机制尚未完全理解。 B-淋巴细胞诱导的成熟蛋白-1（Blimp-1）是正常发育和免疫力必不可少的转录因子7。 Blimp-1在TEFF和Treg细胞11-15中表达，以及在小鼠（Blimp-1CKO）中Blimp-1的T细胞特异性缺失导致严重的肠炎的发展，与结肠中CD4+ T细胞的积累有关，与炎性细胞因子的炎性细胞的产生相关，16、17，17。PrimpymorphismIntrimps Intrimps（编码）（编码）（编码），该炎症是炎症性的。 IBD18，19。因此，Blimp-1似乎是TEFF细胞末端分化的关键调节剂，尽管由T细胞中Blimp-1控制的特定转录程序仍然在很大程度上未知。此处提出的研究将检验以下假设：抑制粘膜T细胞抑制炎症表型的采集，因此在维持肠道粘膜稳态中起着非冗余作用。为了检验这一假设，我们将a）表征肠粘膜表达纤毛-1的T细胞，并确定调节Blimp-1表达的机制； b）确定T细胞特异性缺乏Blimp-1导致慢性肠炎的机制； c）确定Blimp-1阻止炎症表型的获取的分子机制。我们预计，这些研究的完成将为炎症效应T细胞分化的基础遗传程序提供新的见解，并将Blimp-1视为导致IBD等长期条件的过程的关键阻碍。