Role of FSTL-1 in Arthritis

FSTL-1 在关节炎中的作用

基本信息

批准号：
8116805
负责人：
Raphael Hirsch
金额：
$ 8.14万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-29 至 2011-09-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): While performing a DNA microarray gene expression analysis in collagen-induced arthritis (CIA), we discovered that a poorly-characterized gene, follistatin-like 1 (FSTL-1), was highly overexpressed in mouse paws during the early stages of arthritis. Especially-high expression was observed at the interface of synovial pannus and eroding bone, suggesting a role in joint destruction. Our Preliminary Studies provide strong evidence for a role for FSTL-1 in arthritis. Over-expression of FSTL-1 in mice resulted in severe paw swelling and arthritis, while neutralization of endogenous FSTL-1 ameliorated arthritis. We have also observed elevated expression of FSTL-1 in synovial tissues of patients with rheumatoid arthritis. Finally, we have now made the surprising observation that FSTL-1 induces maturation of IL-17-producing Th17 cells from naove CD4+ T cells. This finding represents a novel pathway for induction of Th17 cells, which have recently been shown to play a central role in autoimmunity, and whose maturation had previously been thought to require IL- 6 and TGF-. The current application will test the hypothesis that FSTL-1 plays a central role in arthritis and will explore the possibility that neutralization of FSTL-1 represents a novel therapeutic approach to the treatment of arthritis. The first Specific Aim is to determine the mechanism by which FSTL-1 induces inflammation. We will determine how FSTL-1 induces Th17 cells in vitro, whether FSTL-1 acts by a T cell receptor-dependent or independent pathway, whether FSTL-1 mediates its effect through a cell surface receptor, the FSTL-1 domain(s) responsible for the activity of FSTL-1 and whether FSTL-1 induces Th17 cells in vivo. The second Specific Aim is to determine the factors regulating FSTL-1 expression, including the tissue and cellular sources of FSTL-1 and the signals that induce FSTL-1 expression. The third Specific Aim is to determine the role of FSTL-1 in arthritis by overexpressing it, by neutralizing it in vivo with antibodies as well as by creating a conditional knockout. Understanding the properties of this novel protein will result in a better understanding of arthritis and possibly lead to new therapeutic targets. PUBLIC HEALTH RELEVANCE We have discovered a protein that plays a novel role in arthritis. Characterization of the properties of this protein is likely to lead to a better understanding of arthritis and possibly new therapies.

描述（由申请人提供）：在对胶原诱导的关节炎 (CIA) 进行 DNA 微阵列基因表达分析时，我们发现一种特征较差的基因，卵泡抑素样 1 (FSTL-1)，在小鼠爪子中高度过表达。关节炎的早期阶段。在滑膜血管翳和侵蚀骨的界面处观察到特别高的表达，表明在关节破坏中发挥作用。我们的初步研究为 FSTL-1 在关节炎中的作用提供了强有力的证据。小鼠体内 FSTL-1 的过度表达会导致严重的爪子肿胀和关节炎，而中和内源性 FSTL-1 可改善关节炎。我们还观察到类风湿关节炎患者滑膜组织中 FSTL-1 的表达升高。最后，我们现在做出了令人惊讶的观察，即 FSTL-1 诱导新生 CD4+ T 细胞产生 IL-17 的 Th17 细胞成熟。这一发现代表了一种诱导 Th17 细胞的新途径，Th17 细胞最近被证明在自身免疫中发挥着核心作用，并且以前认为其成熟需要 IL-6 和 TGF-β。目前的申请将检验 FSTL-1 在关节炎中发挥核心作用的假设，并将探索中和 FSTL-1 代表治疗关节炎的新治疗方法的可能性。第一个具体目标是确定 FSTL-1 诱导炎症的机制。我们将确定 FSTL-1 如何在体外诱导 Th17 细胞，FSTL-1 是否通过 T 细胞受体依赖性或独立途径发挥作用，FSTL-1 是否通过细胞表面受体（FSTL-1 结构域）介导其作用负责 FSTL-1 的活性以及 FSTL-1 是否在体内诱导 Th17 细胞。第二个具体目标是确定调节FSTL-1表达的因素，包括FSTL-1的组织和细胞来源以及诱导FSTL-1表达的信号。第三个具体目标是通过过度表达 FSTL-1、用抗体在体内中和它以及通过创建条件敲除来确定 FSTL-1 在关节炎中的作用。了解这种新型蛋白质的特性将有助于更好地了解关节炎，并可能产生新的治疗靶点。公共卫生相关性我们发现了一种在关节炎中发挥新作用的蛋白质。这种蛋白质特性的表征可能会导致人们更好地了解关节炎和可能的新疗法。