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Interplay between Type I IFN and TGF-beta signaling in systemic sclerosis

I 型 IFN 和 TGF-β 信号在系统性硬化症中的相互作用

基本信息

批准号：
8639482
负责人：
Giuseppina Alessandra Farina
金额：
$ 8.02万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639482
关键词：
Autoimmune Diseases Biological Biological Process Cells Cicatrix Clinical Clinical Trials Cutaneous Dermal Diffuse Disease Equilibrium Fibroblasts Fibrosis Gastrointestinal tract structure Gene Expression Gene Targeting Genes Genetic Genetic Polymorphism Goals Grant Human Immune Immune System Diseases Immune response Impairment Inflammation Inflammatory Interferon Receptor Interferon Type I Interferon-beta Interferons Kidney Ligands Link Lung MADH7 gene Measures Mediating Mediator of activation protein Medicine Messenger RNA Mus NF-kappa B Natural Immunity Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Phosphorylation Physiological Play Production Receptor Activation Regulatory Pathway Risk Role STAT4 gene Signal Pathway Signal Transduction Signal Transduction Pathway Skin Systemic Scleroderma Testing Transforming Growth Factor beta Wild Type Mouse base design human TLR3 protein immune activation in vivo inhibitor/antagonist innovation interferon alpha receptor novel programs receptor research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Although it is generally agreed that transforming growth factor-beta (TGF¿) plays a central role in sustaining fibrosis in systemic sclerosis (SSc), the triggers of TGF¿, TGF¿ activation and TGF¿ intracellular signaling are still unknown. The goal of this grant is to understand how TGF¿ signal activation is up-regulated in SSc focusing on the link between innate immunity, inflammation and fibrosis. New emerging evidence points to the importance of innate immunity and interferons (IFNs) in many autoimmune diseases including SSc, and we found that in addition to upregulated TGF¿ gene expression SSc skin and peripheral blood mononuclear cells (PBMC) also show upregulated IFN gene expression. Interestingly more recently we found that polyIC, a toll like receptor 3 (TLR3) ligand, activates human fibroblasts (fb), inducing not only genes known to be regulated by IFNs but also genes that are induced by TGF¿, suggesting that TGF¿ activation and then fibrosis is regulated by the innate immune response. Thus this application proposes to investigate how innate immune activation regulates inflammation and scarring through cross talk between IFN¿/¿and TGF¿. One of the most exciting of our preliminary results is that polyIC and IFN¿ both induce Smad1 phosphorylation, indicating crossactivation of TGF¿ signaling by IFN¿/¿. In addition we unexpectedly discovered that IFN¿ a receptor 2 (IFNAR2) in mice deficient of the IFN¿ receptor 1 (IFNAR1 -/-) activates a "non classical" IFN¿/¿ pathway, and that this pathway may be involved in entirely new biological functions such as controlling the induction of TGF¿ signaling components. In the first aim, proposed experiments will examine the mechanism controlling the physiologic balance between the induction and suppression of the pro-inflammatory program through cross talk between IFN and TGF¿ in fb from wild type (WT) mice, studying Smad1/2/3 expression and phosphorylation, IRF7 and Smad7 gene expression. Then we will investigate the consequences of aberrant IFN signaling that promote novel cross talk between IFN and TGF¿, and causing the modified equilibrium in TLR activation promoting the profibrotic phenotype in fb from IFNAR1-/- mice. Aim 2 will explore whether impairment of IFN¿/¿ signaling might underlie the pro-fibrotic phenotype that characterizes SSc fb, as we observed in IFNAR1 -/- fb. Experiments in this aim will test the effect of IFN¿ and polyIC on TGF¿ signaling components and the functioning of INF¿/¿ signaling in SSc compared to normal fb. Finally we will examine the in vivo expression of selected IFN¿/¿ and TGF¿ mediators IRF7 and Smad7, in SSc and control skin. Together, these results should significantly extend our understanding of the role of innate immune activation, IFNs and TGF¿ in dermal fibrosis, enlightening a new standpoint of SSc pathogenesis that IFN¿/¿ impairment might be the primary cause of uncontrolled TGF¿ activation. In addition the new finding of IFNAR2 function in controlling activation of TGF¿ signaling, add a novel biological response to the complexity of IFN-mediated signaling potentially influencing the clinical use of therapeutics targeting IFNs not only in SSc but also in other diseases.

描述（由申请人提供）：尽管人们普遍认为转化生长因子-β（TGF-β）在维持系统性硬化症（SSc）的纤维化中起着核心作用，但TGF-β、TGF-β活化和TGF-β细胞内信号传导的触发因素仍然未知。这项资助的目标是了解TGF信号激活如何在SSc中上调，重点是先天免疫，炎症和纤维化之间的联系。新出现的证据指出先天免疫和干扰素（IFN）在许多自身免疫性疾病（包括SSc）中的重要性，我们发现，除了上调TGF？基因表达外，SSc皮肤和外周血单核细胞（PBMC）也显示上调IFN基因表达。有趣的是，最近我们发现多聚IC，一种toll样受体3（TLR 3）配体，激活人成纤维细胞（fb），不仅诱导已知由IFN调节的基因，而且诱导由TGF β诱导的基因，表明TGF β激活，然后纤维化是由先天免疫反应调节的。因此，本申请提出研究先天免疫激活如何通过IFN/γ和TGF/γ之间的串扰调节炎症和瘢痕形成。我们的初步结果中最令人兴奋的一个是polyIC和IFN <$$>都诱导Smad 1磷酸化，表明IFN <$/<$交叉激活TGF <$信号。此外，我们意外地发现，在IFN <$受体1（IFNAR 1-/-）缺陷的小鼠中，IFN <$a受体2（IFNAR 2）激活“非经典”IFN <$/<$途径，并且该途径可能涉及全新的生物学功能，例如控制TGF <$信号传导组分的诱导。在第一个目标中，提出的实验将通过野生型（WT）小鼠的fb中IFN和TGF β之间的串扰来检查控制促炎程序的诱导和抑制之间的生理平衡的机制，研究Smad 1/2/3表达和磷酸化、IRF 7和Smad 7基因表达。然后，我们将研究异常IFN信号传导的后果，其促进IFN和TGF β之间的新型串扰，并导致TLR活化中的改良平衡，促进IFNAR 1-/-小鼠fb中的促纤维化表型。目的2将探讨IFN <$/<$信号传导的损伤是否可能是SSc fb的促纤维化表型的基础，正如我们在IFNAR 1-/- fb中观察到的那样。为此目的的实验将测试IFN <$和polyIC对TGF <$信号传导组分的影响以及与正常fb相比SSc中INF <$/<$信号传导的功能。最后，我们将检查选定的IFN/β和TGF β介体IRF 7和Smad 7在SSc和对照皮肤中的体内表达。总之，这些结果应显着扩展我们的理解的作用，先天免疫激活，IFN和TGF <$在皮肤纤维化，启发了一个新的观点，SSc发病机制，IFN <$/<$损伤可能是不受控制的TGF <$激活的主要原因。此外，IFNAR 2在控制TGF β信号传导激活中的功能的新发现，为IFN介导的信号传导的复杂性增加了新的生物学应答，这可能影响靶向IFN的治疗剂不仅在SSc中而且在其他疾病中的临床使用。