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的慢性复发性炎症性疾病，统称为炎症性肠病（IBD）。IBD的病因在美国影响了大约140万人，但在很大程度上仍然未知。促炎细胞因子在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（TNF）由于其位于炎症和免疫调节级联反应的顶点而受到最大的关注。TNF抑制剂，如Remicade和Enbrel，已被接受为治疗各种炎症性疾病，包括克罗恩病和溃疡性结肠炎的有效方法。然而，它们的副作用和高成本促使人们研究新的替代治疗方式。一种这样的替代物是长期已知的抗炎生长因子，颗粒蛋白前体（PGRN），其最近才在我们的全球遗传筛选中被发现是TNF受体（TNFR）的新型配体。我们最近报道，PGRN拮抗TNF活性，并显着减轻或改善实验诱导的小鼠炎症性关节炎。更重要的是，Atsttrin，一种由三个PGRN片段组成的工程蛋白，在体内表现出高度有效的抗炎活性，超过了PGRN本身。使用PGRN缺陷小鼠，我们在我们的初步研究中证明，PGRN基因的缺失使B6小鼠更容易受到葡聚糖硫酸钠（DSS）诱导，并发展成更严重的结肠炎。此外，PGRN拮抗TNF-α介导的Treg抑制功能和Foxp 3表达的下调;用PGRN进行的体内治疗选择性地刺激Treg细胞中的IL-10产生，并且如果IL-10信号传导被阻断，则PGRN刺激的Treg抑制功能在很大程度上丧失。这些研究导致了中心假设，即PGRN通过其与TNFR的相互作用和在炎性肠病过程中刺激产生IL-10的Treg细胞来发挥其保护作用。这一假设将在三个特定的目的进行测试：（1）PGRN介导的信号传导和分子事件是否取决于PGRN与TNF/TNFR在THP和炎症性肠病中的相互作用？(2)IL-10是炎症性肠病发病机制中PGRN作用的关键介质吗？(3)重组PGRN，特别是其衍生的Atsttrin，能否直接用于治疗炎症性肠病？该研究的成功完成不仅有助于我们对IBD发病机制的理解，而且还有助于开发新的抗TNF/TNFR治疗干预措施，用于各种TNF相关疾病，包括IBD。.

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. .