Progranulin Intervention in Inflammatory Bowel Diseases

描述（由申请人提供）：溃疡性结肠炎和克罗恩病是胃肠道慢性，复发性炎症性疾病，统称为炎症性肠病（IBD）。在美国，大约有140万人受到IBD的影响，病因在很大程度上仍然未知。促炎细胞因子被认为在IBD的发病机制中起重要作用。在这些细胞因子中，肿瘤坏死因子（tumor necrosis factor， TNF）因其处于炎症和免疫调节级联的顶端而受到最大的关注。TNF抑制剂，如Remicade和Enbrel，已被认为是治疗各种炎症性疾病的有效方法，包括克罗恩病和溃疡性结肠炎。然而，它们的副作用和高昂的费用促使人们研究新的替代治疗方式。其中一种替代方法是众所周知的抗炎生长因子，前颗粒蛋白（PGRN），它最近才在我们的全球遗传筛选中被发现是TNF受体（TNFR）的一种新型配体。我们最近报道了PGRN拮抗TNF活性，并显著减轻或改善小鼠实验诱导的炎性关节炎。更重要的是，atstrin是一种由三个PGRN片段组成的工程蛋白，在体内表现出比PGRN本身更强的抗炎活性。使用PGRN缺陷小鼠，我们在初步研究中证明，PGRN基因的缺失使B6小鼠更容易受到葡聚糖硫酸钠（DSS）的诱导，并发生更严重的结肠炎。此外，PGRN可拮抗TNF介导的Treg抑制功能下调和Foxp3表达；在体内，PGRN选择性地刺激Treg细胞中IL-10的产生，如果IL-10信号被阻断，PGRN刺激的Treg抑制功能在很大程度上丧失。这些研究导致了PGRN在炎症性肠病过程中通过与TNFR的相互作用和刺激IL-10产生Treg细胞发挥其保护作用的中心假设。这一假设将在三个特定目标中得到验证：(1)在Tregs和炎症性肠病中，PGRN介导的信号和分子事件是否依赖于PGRN与TNF/TNFR的相互作用？(2) IL-10是否在炎症性肠病发病过程中是PGRN作用的关键介质？(3)重组PGRN，尤其是其衍生品阿司特林能否直接应用于炎症性肠病的治疗？本研究的成功完成，不仅有利于我们对IBD发病机制的认识，而且有助于开发新的抗tnf /TNFR治疗干预措施，治疗包括IBD在内的各种tnf相关疾病。

DESCRIPTION (provided by applicant): Ulcerative colitis and Crohn's disease are chronic, relapsing inflammatory disorders of the gastrointestinal tract, collectively known as Inflammatory Bowel Disease (IBD). The cause of IBD, which in the U.S. affects an estimated 1.4 million individuals, remains largely unknown. Pro-inflammatory cytokines are believed to play important roles in the pathogenesis of IBD. Among these cytokines, tumor necrosis factor (TNF) has received the greatest attention because of its position at the apex of the inflammatory and immune-regulatory cascades. TNF inhibitors, such as Remicade and Enbrel, have been accepted as an effective approach to treating various kinds of inflammatory diseases, including Crohn's disease and ulcerative colitis. However, their side effects and high cost prompt investigations into new, alternative treatment modalities. One such alternative is a long- known anti-inflammatory growth factor, progranulin (PGRN), which was only recently discovered to be a novel ligand of TNF receptors (TNFR) in our global genetic screen. We recently reported that PGRN antagonizes TNF activity and significantly attenuates or ameliorates experimentally induced inflammatory arthritis in mice. More importantly, Atsttrin, an engineered protein composed of three PGRN fragments, exhibited highly potent anti-inflammatory activity, which surpassed PGRN itself, in vivo. Using PGRN deficient mice, we demonstrated in our preliminary studies that the deletion of the PGRN gene renders B6 mice more susceptible to Dextran Sulfate Sodium (DSS) induction and to developing more severe colitis. In addition, PGRN antagonizes TNF¿- mediated down-regulation of Treg suppressive function and Foxp3 expression; in vivo treatment with PGRN selectively stimulates IL-10 production in Treg cells and PGRN-stimulated Treg suppressive function is largely lost if IL-10 signaling is blocked. These studies have led to the central hypothesis that PGRN exerts its protective effects through its interaction with TNFR and the stimulation of IL-10 producing Treg cells in the course of inflammatory bowel disease. This hypothesis will be tested in three Specific Aims: (1) Do PGRN-mediated signaling and molecular events depend on PGRN's interaction with TNF/TNFR in Tregs and in inflammatory bowel disease? (2) Is IL-10 a critical mediator of PGRN action in the pathogenesis of inflammatory bowel disease? (3) Can recombinant PGRN, especially its derived Atsttrin, be directly applied to treat inflammatory bowel disease? Successful completion of the proposed research will not only benefit our understanding of the pathogenesis of IBD, but also lead to the development of new anti-TNF/TNFR therapeutic interventions for various kinds of TNF-related diseases, including IBD. .