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）：肠粘膜稳态的维持是通过复杂的机制实现的，包括免疫应答的主动下调1，2。这些机制的破坏导致对肠道植物群的慢性免疫应答，这可能导致炎症性肠病（IBD）的发展，3，4并且还可能导致肠外部位的自身免疫性疾病5，6。CD 4 +T辅助效应细胞（Teff）和调节性（Treg）淋巴细胞是维持肠粘膜稳态的重要参与者2，但其在肠粘膜稳态和炎症条件下功能的分子机制尚未完全了解。B淋巴细胞诱导成熟蛋白-1（Blimp-1）是正常发育和免疫所必需的转录因子7。Blimp-1在Teff和Treg细胞中表达11 -15，小鼠中Blimp-1的T细胞特异性缺失（Blimp-1CKO）导致严重肠道炎症的发展11，与结肠中CD 4 + T细胞的积累和炎性细胞因子的异常产生相关11，16，17。PRDM 1（编码Blimp-1）的多态性与人类严重炎症性疾病（包括IBD）相关18，19。因此，Blimp-1似乎是Teff细胞终末分化的关键调节因子，尽管Blimp-1在T细胞中控制的特异性转录程序在很大程度上仍然未知。这里提出的研究将检验这样的假设：Blimp-1是抑制粘膜T细胞获得炎症表型所必需的，因此在维持肠粘膜稳态方面发挥着非多余的作用。为了检验这一假设，我们将a）表征肠粘膜中表达Blimp-1的T细胞并确定调节Blimp-1表达的机制; B）鉴定T细胞特异性缺乏Blimp-1导致慢性肠道炎症的机制;和c）确定Blimp-1防止获得炎性表型的分子机制。我们预计，这些研究的完成将为炎症效应T细胞分化的遗传程序提供新的见解，并暗示Blimp-1是导致IBD等慢性疾病过程的关键抑制因子。