Regulation and Function of Interleukin-7 in Primary Sjogrens Syndrome

白介素7在原发性干燥综合征中的调控及作用

基本信息

批准号：
8614323
负责人：
Qing Yu
金额：
$ 48.05万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8614323
关键词：
Adaptor Signaling Protein Affect American Antibodies Autoimmune Diseases Basic Science CXCL10 gene Cell Line Cells Cessation of life Chronic Clinical Research Development Disease Disease model Down-Regulation Epithelial Cells Florida Foundations Functional disorder Gene Silencing Goals Health Human IRF1 gene Immune In Vitro Individual Inflammation Interferons Interleukin 7 Receptor Interleukin-7 Laboratories Lacrimal gland structure Mediating Mediator of activation protein Modeling Molecular Mus Mutant Strains Mice Onset of illness Pathogenesis Pathway interactions Patients Personal Satisfaction Play Production Publications Receptor Signaling Regulation Reporting Research Role STAT1 gene Salivary Glands Signal Pathway Signal Transduction Sjogren&apos s Syndrome Staging Symptoms T-Lymphocyte TNF receptor-associated factor 1 Testing Therapeutic Tumor Necrosis Factor-alpha Universities Xerostomia chronic autoimmune disease cytokine cytotoxic eye dryness in vivo mouse model novel diagnostics novel therapeutics programs receptor response systemic autoimmune disease translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Sjogren's syndrome (SjS) is a chronic autoimmune disease that affects 2-4 million Americans and greatly affects the health and well-being of the patients. SjS is characterized by chronic inflammation and dysfunction of the salivary and lacrimal glands with dry mouth and dry eyes as the primary symptoms. Autoreactive effector T cells and T cell-derived cytokines play a crucial role in the development and onset of SjS. Interleukin-7 (IL-7) plays a crucial pathogenic role in multiple autoimmune diseases through enhancing T helper (Th) 1 and T cytotoxic (Tc) 1 responses. Elevated IL-7 levels were reported in primary SjS patients. Our preliminary studies showed that both exogenous and endogenous IL-7 promotes the development and onset of SjS in a mouse disease model, which is accompanied by enhanced Th1 and Tc1 responses. In addition, we found that IFN-α and IFN-γ can induce IL-7 production in a human salivary gland cell line. In the current study, we will characterize the in vivo functions of IL-7 and its targets in the development and the persistence of primary SjS, and define the signaling and molecular pathways that cause excessive IL-7 production in SjS. In Aim 1 of this study, we will assess the in vivo functions of IL-7 and IL-7-induced Th1/Tc1 cytokines in the development of SjS and in the persistence of SjS after disease onset. We will use in vivo antibody blockade approach to abrogate IL-7, IFN-γ or TNF-α activity at specific stages of the disease in C57BL/6.NOD-Aec1Aec2 mice, a well-defined model of primary SjS. In Aim 2, we will determine the molecular mechanisms by which IL-7 enhances Th1/Tc1 responses. We will use several genetically mutant mice, in vivo antibody blockade and in vitro gene-silencing approaches to determine the role of T-bet, PD-1 and TRAF1 in IL-7-mediated enhancement of Th1/Tc1 responses. Moreover, we will collaborate with Dr. Seunghee Cha at the University of Florida to validate these results in human T cells from SjS patients and healthy controls, using in vitro T cell stimulation cultures and gene-silencing approaches. In Aim 3, we will characterize the signaling pathways that cause excessive IL-7 production in salivary gland cells in SjS. We will use several genetically mutant mice, a human epithelial cell line and a combination of in vivo and in vitro approaches to characterize the in vivo role of IFN-α and IFN-γ in enhancing IL-7 production from salivary gland cells in the SjS setting. Completion of this project will provide crucial information and foundation for the development of novel diagnostic and therapeutic strategies for SjS by targeting IL-7 and Th1/Tc1 cytokines.

描述（由申请人提供）：干燥综合征（SjS）是一种慢性自身免疫性疾病，影响着 2-400 万美国人，极大地影响患者的健康和福祉。 SjS 的特征是唾液腺和泪腺的慢性炎症和功能障碍。以口干和眼干为主要症状的腺体，自身反应性效应 T 细胞和 T 细胞衍生的细胞因子在 SjS 的发生和发病中发挥着至关重要的作用。 (IL-7) 通过增强 T 辅助细胞 (Th) 1 和 T 细胞毒性 (Tc) 1 反应在多种自身免疫性疾病中发挥重要的致病作用。我们的初步研究表明，原发性 SjS 患者的 IL-7 水平升高。在小鼠疾病模型中，内源性IL-7促进SjS的发生和发生，并伴有Th1和Tc1反应增强。此外，我们发现IFN-α和IFN-γ可以诱导IL-7。在当前的研究中，我们将描述 IL-7 及其在原发性 SjS 的发育和持续过程中的靶标的体内功能，并确定导致过量 IL-7 的信号传导和分子途径。 SjS 中 7 的产生在本研究的目标 1 中，我们将评估 IL-7 和 IL-7 诱导的 Th1/Tc1 细胞因子在 SjS 发生和疾病发作后 SjS 持续存在中的体内功能。体内使用在 C57BL/6.NOD-Aec1Aec2 小鼠（一种明确的原发性 SjS 模型）中，使用抗体阻断方法消除疾病特定阶段的 IL-7、IFN-γ 或 TNF-α 活性。 IL-7 增强 Th1/Tc1 反应的分子机制我们将使用几种基因突变小鼠、体内抗体阻断和体外基因沉默方法来确定 T-bet 的作用。此外，我们将与佛罗里达大学的 Seunghee Cha 博士合作，在来自 SjS 患者和健康对照的人类 T 细胞中验证这些结果。体外 T 细胞刺激培养和基因沉默方法在目标 3 中，我们将描述导致 SjS 唾液腺细胞产生过多 IL-7 的信号通路。一个结合体内和体外方法来表征 IFN-α 和 IFN-γ 在 SjS 环境中增强唾液腺细胞产生 IL-7 的体内作用，该项目的完成将为开发提供重要的信息和基础。通过针对 IL-7 和 Th1/Tc1 细胞因子的 SjS 新型诊断和治疗策略。