Investigating the Requirement for Tbet Expression during Psoriasis

调查银屑病期间 Tbet 表达的要求

• 批准号: 7677176
• 负责人: LAURIE E HARRINGTON
• 金额: $ 5.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677176
• 关键词: Animal Model; Autoimmune Process; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Colitis; Data; Development; Disease; Experimental Autoimmune Encephalomyelitis; Experimental Models; Feasibility Studies; Immune response; Individual; Inflammation; Inflammatory; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Mediating; Mediator of activation protein; Modeling; Molecular; Multiple Sclerosis; Pathology; Patients; Population; Production; Property; Psoriasis; Research; Research Design; Rheumatoid Arthritis; Role; STAT4 gene; Signal Transduction; Site; T-Lymphocyte; Th2 Cells; base; cytokine; design; interleukin-22; interleukin-23; macrophage; mouse model; new therapeutic target; pathogen; programs; response; skin disorder; therapeutic target; transcription factor

For over a decade, a number of chronic inflammatory disorders including multiple sclerosis, rheumatoid arthritis, and psoriasis have been described as Th1 -mediated disorders because IFNy-producing CD4 T cells are prevalent in diseased patients and IFNy strongly activates macrophages, potentiating inflammation. However recent data from animal models of numerous autoimmune/chronic inflammatory disorders suggests that Th17 effector CD4 T cells are responsible for the induction of disease. Interestingly, the onset of these chronic inflammatory diseases is associated with elevated numbers of both IFNy+ and IL-17+ effector CD4 T cells at the sites of inflammation, opening the debate on the individual roles of these effector CD4 T cell populations during disease. In fact, the impact of Th1 CD4 T cells on the development of psoriasis remains unclear. Under certain experimental conditions, psoriasis can be induced by IL-12 stimulation and this pathology is associated with increased levels of IFNy, although it has been demonstrated that IFNy is not essential to drive disease. The Th1-associated transcription factors Tbet and STAT4 are required to induce some experimental models of chronic inflammation, such as EAE and colitis, even when IFNy is not. To date, little is known about the role of these transcriptional regulators during the development of psoriasis. We hypothesize that Tbet and STAT4, Th1-associated transcription factors, are necessary for the development of psoriasis mediated by CD4 T cells. We propose the following specific aims to determine the role of Tbet and STAT4 during two models of psoriasis mediated by distinct effector mechanisms. Aim 1. Tbet is required for the development of psoriasis. Aim 2. STAT4 signaling is critical for the onset of psoriasis. Collectively, these studies are designed to provide new information regarding the molecular mechanisms of CD4 T cell-mediated psoriasis. The findings from these studies may identify new potential targets for therapeutic and/or preventative strategies designed to ablate psoriasis, as well as other chronic inflammatory disorders.

十多年来，许多慢性炎症性疾病，包括多发性硬化症，类风湿病 关节炎和牛皮癣已被描述为Th1介导的疾病，因为产生的CD4 T细胞 患病患者普遍存在，IFNY强烈激活巨噬细胞，增强炎症。 但是，来自众多自身免疫/慢性炎症性疾病的动物模型的最新数据表明 Th17效应子CD4 T细胞负责诱导疾病。有趣的是，这些发作 慢性炎症性疾病与IFNY+和IL-17+效应的CD4 T的数量增加有关 炎症部位的细胞，就这些效应子CD4 T细胞的各个角色的辩论开放 疾病期间的种群。实际上，Th1 CD4 T细胞对牛皮癣发展的影响仍然存在 不清楚。在某些实验条件下，牛皮癣可以通过IL-12刺激诱导，这 病理学与IFNY水平升高有关，尽管已经证明IFNY不是 驱动疾病必不可少的。需要Th1相关的转录因子TBET和STAT4才能诱导 即使不是IFNY，一些慢性炎症的实验模型，例如EAE和结肠炎。到 日期，对于这些转录调节剂在牛皮癣发展过程中的作用知之甚少。 我们假设TBET和STAT4，Th1相关的转录因子是必要的 CD4 T细胞介导的牛皮癣的发展。我们提出以下具体目的来确定 TBET和STAT4在由不同的效应器机制介导的两种牛皮癣模型中的作用。 目的1。TBET是牛皮癣发展所必需的。 AIM2。STAT4信号对于牛皮癣的发作至关重要。 总的来说，这些研究旨在提供有关分子机制的新信息 CD4 T细胞介导的牛皮癣。这些研究的发现可能会确定 旨在消除牛皮癣的治疗和/或预防性策略以及其他慢性炎症 疾病。