Role of FSTL-1 in Arthritis

描述(申请人提供)：在进行胶原诱导性关节炎(CIA)的DNA微阵列基因表达分析时，我们发现在关节炎的早期阶段，一个特征不佳的基因--卵泡抑素样蛋白1(FSTL-1)在小鼠足爪中高度过度表达。在滑膜血管膜与侵蚀骨的交界处有特别高的表达，提示其在关节破坏中起作用。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。在小鼠中过表达FSTL-1会导致严重的足爪肿胀和关节炎，而内源性FSTL-1的中和可以改善关节炎。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，我们现在已经做出了令人惊讶的观察，FSTL-1诱导NAVE CD4+T细胞中产生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，最近发现Th17细胞在自身免疫中发挥核心作用，并且其成熟之前被认为需要IL-6和转化生长因子-1。目前的应用将检验FSTL-1在关节炎中发挥核心作用的假设，并将探索中和FSTL-1代表治疗关节炎的一种新的治疗方法的可能性。第一个具体目标是确定FSTL-1引起炎症的机制。我们将确定FSTL-1在体外如何诱导Th17细胞，FSTL-1是否通过T细胞受体依赖或独立途径发挥作用，FSTL-1是否通过细胞表面受体介导其作用，FSTL-1结构域(S)负责FSTL-1的活性，以及FSTL-1是否在体内诱导Th17细胞。第二个特定目的是确定调控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，通过在体内用抗体中和它，以及通过创建条件基因敲除来确定FSTL-1在关节炎中的作用。了解这种新蛋白质的性质将有助于更好地了解关节炎，并可能导致新的治疗靶点。公共卫生相关性我们发现了一种蛋白质，它在关节炎中扮演着新的角色。对这种蛋白质特性的表征可能会导致对关节炎的更好理解，并可能导致新的治疗方法。

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.