Role of FSTL-1 in Arthritis

描述（由申请人提供）：当在胶原诱导的关节炎（CIA）中进行DNA微阵列基因表达分析时，我们发现一种表征不佳的基因卵泡抑素样1（FSTL-1）在关节炎的早期阶段在小鼠爪中高度过表达。在滑膜血管翳和侵蚀骨的界面观察到特别高的表达，表明在关节破坏中的作用。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。FSTL-1在小鼠中的过表达导致严重的爪肿胀和关节炎，而内源性FSTL-1的中和可改善关节炎。我们还观察到FSTL-1在类风湿性关节炎患者的滑膜组织中表达升高。最后，我们现在已经做出了令人惊讶的观察结果，即FSTL-1诱导产生IL-17的Th 17细胞从原始CD 4 + T细胞成熟。这一发现代表了一种新的诱导Th 17细胞的途径，Th 17细胞最近已被证明在自身免疫中发挥核心作用，并且其成熟以前被认为需要IL- 6和TGF-β。本申请将测试FSTL-1在关节炎中起核心作用的假设，并将探索FSTL-1的中和代表治疗关节炎的新治疗方法的可能性。第一个具体目的是确定FSTL-1诱导炎症的机制。我们将确定FSTL-1如何在体外诱导Th 17细胞，FSTL-1是否通过T细胞受体依赖性或非依赖性途径起作用，FSTL-1是否通过细胞表面受体介导其作用，负责FSTL-1活性的FSTL-1结构域以及FSTL-1是否在体内诱导Th 17细胞。第二个具体目标是确定FSTL-1表达的调节因子，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表达FSTL-1，通过在体内用抗体中和它以及通过产生条件性敲除来确定FSTL-1在关节炎中的作用。了解这种新蛋白质的特性将有助于更好地了解关节炎，并可能导致新的治疗靶点。我们发现了一种在关节炎中发挥新作用的蛋白质。这种蛋白质的特性的表征可能会导致更好地了解关节炎和可能的新疗法。

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.